Trna synthetase inhibitors

ABSTRACT

Disclosed herein are secondary amine compounds that inhibit tRNA synthetase. The compounds of the invention are useful in inhibiting tRNA synthetase in Gram-negative bacteria and are useful in killing Gram-negative bacteria. The secondary amine compounds of the invention are also useful in the treatment of tuberculosis.

RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.16/961,516, filed on Jul. 10, 2020, which is the U.S. National Stage ofInternational Application No. PCT/US19/13305, filed on Jan. 11, 2019,published in English, which claims the benefit of U.S. ProvisionalApplication No. 62/616,979, filed on Jan. 12, 2018. The entire teachingsof the above application(s) are incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under U19 AI109764 fromthe National Institute of Allergy and Infectious Disease. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Gram-negative bacteria are intrinsically resistant to many smallmolecules owing to the presence of an outer membrane, which acts as apermeability barrier. tRNA synthetases are involved in proteinbiosynthesis so that inhibition thereof may be expected to lead to acessation of cell growth. Thus, for instance, the compound mupirocin,produced by the organism Pseudomonas fluorescens, is an antibacterialagent and is used as the active ingredient in the product Bactroban,marketed by GlaxoSmithKline. However, mupirocin is only effectiveagainst Gram-positive, but not Gram-negative bacteria. Mupirocin hasbeen shown to be an inhibitor of the isoleucyl tRNA synthetase. EachtRNA synthetase represents a separate target for drug discovery. tRNAsynthetase inhibitors which are selective for bacterial cells overmammalian cells are of considerable therapeutic interest as they havethe potential to be used as antibacterial agents. Thus, there remains aneed to develop compounds having inhibitory activity toward tRNAsynthetase in Gram-negative bacteria.

SUMMARY OF THE INVENTION

In certain aspects, the invention provides a compound of formula (I):

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   each of R¹, R², R³, R⁴, and R⁵ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(b) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R⁸, —O—CH₂—R⁸, and        —O—CH₂CH₂—O—R⁹;    -   or R¹ and R², R² and R³, R³ and R⁴, or R⁴ and R⁵, taken together        with the intervening atoms, form an optionally substituted aryl,        heteroaryl, cycloalkyl, or heterocycloalkyl group;    -   R⁶ is H or (C₁-C₆)alkyl;    -   R⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R⁸ is selected from —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl wherein the        heteroaryl is not 4-pyridinyl, benzimidazole or thiazole,        optionally substituted aryloxy(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,        (C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl,        heteroaryl(C₁-C₈)alkyl, (C₂-C₈)alkoxy, (C₃-C₈)hydroxyalkyl,        (C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₁-C₈)haloalkoxy(C₁-C₈)alkyl,        (C₁-C₈)thioalkoxy(C₁-C₈)alkyl, (CH₃SO₂)(C₁-C₈)alkyl, and        ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(b), independently for each occurrence, is selected from H,        optionally substituted (C₁-C₈)alkyl, optionally substituted        (C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally        substituted aryl, and optionally substituted aryl(C₁-C₈) alkyl;    -   further wherein:    -   at least one of R¹, R², R³, R⁴, and R⁵ is selected from        (C₃-C₈)alkyl, (C₂-C₈)hydroxyalkyl, (C₁-C₈)aminoalkyl, straight        chain (C₂-C₈)alkoxy, (C₁-C₈)haloalkoxy, (C₄-C₈)cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted aryloxy, (C₆-C₁₀)cycloalkoxy,        —OC(O)((C₁-C₈)alkyl), —NHC(O)(aryl), (H₃CSO₂)(C₁-C₈)alkylene,        optionally substituted (R^(b) ₂NSO₂)(C₁-C₈)alkylene,        di((C₁-C₈)alkyl)amino, —NH—CH₂—R⁸, —O—CH₂—R⁸, and        —O—CH₂CH₂—O—R⁹.

In other aspects, the invention provides a compound of formula (II′):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   X is O or S;    -   each of R¹⁰, R¹¹, R¹², and R¹³ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene,        (H₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino;    -   or R¹⁰ and R¹¹, R¹¹ and R¹², or R¹² and R¹³, taken together with        the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl group;    -   R¹⁴ is H or (C₁-C₆)alkyl;    -   R¹⁵ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;

represents a heterocyclic group substituted by oxo (═O) and optionallysubstituted by one or more additional substituents; and

-   -   n is an integer from 1-3.

In further aspects, the invention provides a compound of formula (III′):

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   each of R⁴⁰, R⁴¹, R⁴², and R⁴³ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene,        (H₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino;    -   or R⁴⁰ and R⁴¹, R⁴¹ and R⁴², or R⁴² and R⁴³, taken together with        the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl group;    -   R⁴⁴ is H or (C₁-C₆)alkyl;    -   R⁴⁵ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R^(c), independently for each occurrence, is selected from H,        (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₁-C₈)alkoxyl,        (C₁-C₈)hydroxyalkyl, (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, aryl, and aryl(C₁-C₈) alkyl;    -   R^(d), independently for each occurrence, is selected from H,        optionally substituted —C(O)(C₁-C₈)alkyl, optionally substituted        —C(O)NH—(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, and        optionally substituted aryl(C₁-C₈) alkyl, or    -   two R^(d) are taken together with the nitrogen atom to which        they are attached to form an optionally substituted 5-6-membered        heterocyclyl; and    -   m is an integer from 1-3.

The invention further provides compounds, or pharmaceutically acceptablesalts thereof, of the compounds listed in Table 1.

In other aspects, the invention provides pharmaceutical compositionscomprising a compound of any one of claims 1-38, in combination with apharmaceutically acceptable carrier.

In certain aspects, the invention provides methods of treating abacterial infection in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of theinvention, i.e., a compound of formula (I), formula (II), formula (II′),formula (III), formula (III′), or a compound pictured in Table 1, or apharmaceutical composition comprising the compound.

The invention further provides methods of treating a bacterial infectionin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (IV′):

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   each of R²¹, R²², R²³, R²⁴, and R²⁵ is independently selected        from H, OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂, optionally        substituted —S—(C₁-C₆)alkyl; tri((C₁-C₈)alkyl)silyl, optionally        substituted (C₁-C₈)alkyl, optionally substituted (C₁-C₈)alkoxy,        optionally substituted (C₁-C₈)aminoalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₁-C₈)haloalkyl,        optionally substituted (C₁-C₈)haloalkoxy, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        aryloxy, optionally substituted arylalkoxy, optionally        substituted heteroaryloxy, optionally substituted        heteroarylalkoxy, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted (C₃-C₁₀)cycloalkoxy, optionally        substituted (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(e) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R²⁸, —O—CH₂—R²⁸, and        —O—CH₂CH₂—O—R²⁹;    -   or R²¹ and R²², R²² and R²³, R²³ and R²⁴, or R²⁴ and R²⁵, taken        together with the intervening atoms, form an optionally        substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        group;    -   R²⁶ is H or (C₁-C₆)alkyl;    -   R²⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R²⁸ is selected from H, —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl, optionally        substituted aryl, optionally substituted aryloxy(C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, (C₂-C₉)heterocycloalkyl,        (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl, heteroaryl(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, (C₂-C₈)hydroxyalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        (C₁-C₈)haloalkoxy(C₁-C₈)alkyl, (C₁-C₈)thioalkoxy(C₁-C₈)alkyl,        (CH₃SO₂)(C₁-C₈)alkyl, and ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R²⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(e), independently for each occurrence, is selected from H,        optionally substituted —C(O)(C₁-C₈)alkyl, optionally substituted        —C(O)NH—(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, and        optionally substituted aryl(C₁-C₈) alkyl, or    -   two R^(e) are taken together with the nitrogen atom to which        they are attached to form an optionally substituted 5-6-membered        heterocyclyl;    -   further wherein:

if R²⁶ is (C₁-C₆)alkyl and R²⁷ is (C₆)cycloalkyl, then R²¹ and R²⁵ arenot OH, —OC(O)((C₁-C₈)alkyl), optionally substituted (C₁-C₈)alkoxy,optionally substituted (C₁-C₈)haloalkoxy, optionally substitutedaryloxy, optionally substituted arylalkoxy, optionally substitutedheteroaryloxy, optionally substituted heteroarylalkoxy, optionallysubstituted (C₃-C₁₀)cycloalkoxy, optionally substituted(C₂-C₉)heterocycloalkoxy, —O—CH₂—R²⁸, or —O—CH₂CH₂—O—R²⁹.

In certain aspects, the invention provides methods of treatingtuberculosis, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of the invention, i.e., acompound of formula (I), formula (II), formula (II′), formula (III),formula (III′), or a compound pictured in Table 1, or a pharmaceuticalcomposition comprising the compound.

The invention further provides methods of treating tuberculosis,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (V′):

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   each of R³¹, R³², R³³, R³⁴, and R³⁵ is independently selected        from H, OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂, optionally        substituted —S—(C₁-C₆)alkyl; tri((C₁-C₈)alkyl)silyl, optionally        substituted (C₁-C₈)alkyl, optionally substituted (C₁-C₈)alkoxy,        optionally substituted (C₁-C₈)aminoalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₁-C₈)haloalkyl,        optionally substituted (C₁-C₈)haloalkoxy, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        aryloxy, optionally substituted arylalkoxy, optionally        substituted heteroaryloxy, optionally substituted        heteroarylalkoxy, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted (C₃-C₁₀)cycloalkoxy, optionally        substituted (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(f) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R³⁸, —O—CH₂—R³⁸, and        —O—CH₂CH₂—O—R³⁹;    -   or R³¹ and R³², R³² and R³³, R³³ and R³⁴, or R³⁴ and R³⁵, taken        together with the intervening atoms, form an optionally        substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        group;    -   R³⁶ is H or (C₁-C₆)alkyl;    -   R³⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R³⁸ is selected from H, —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl, optionally        substituted aryl, optionally substituted aryloxy(C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, (C₂-C₉)heterocycloalkyl,        (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl, heteroaryl(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, (C₂-C₈)hydroxyalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        (C₁-C₈)haloalkoxy(C₁-C₈)alkyl, (C₁-C₈)thioalkoxy(C₁-C₈)alkyl,        (CH₃SO₂)(C₁-C₈)alkyl, and ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R³⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(f), independently for each occurrence, is selected from H,        optionally substituted —C(O)(C₁-C₈)alkyl, optionally substituted        —C(O)NH—(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, and        optionally substituted aryl(C₁-C₈) alkyl, or    -   two R^(f) are taken together with the nitrogen atom to which        they are attached to form an optionally substituted 5-6-membered        heterocyclyl.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing will be apparent from the following more particulardescription of example embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingembodiments of the present invention.

FIG. 1 shows that the compounds of the invention, such as B1, can beused in combination with other tRNA synthetase inhibitors in order toovercome antibiotic resistance.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery of a class of compoundswith surprising antibacterial activity. A description of exampleembodiments of the invention follows.

Definitions

“Alkyl” means an optionally substituted saturated aliphatic branched orstraight-chain monovalent hydrocarbon radical having the specifiednumber of carbon atoms. Thus, “(C₁-C₆) alkyl” means a radical havingfrom 1-6 carbon atoms in a linear or branched arrangement.“(C₁-C₆)alkyl” includes methyl, ethyl, propyl, butyl, pentyl and hexyl.

“Alkylene” means an optionally substituted saturated aliphatic branchedor straight-chain divalent hydrocarbon radical having the specifiednumber of carbon atoms. Thus, “(C₁-C₆)alkylene” includes a divalentsaturated aliphatic radical having from 1-6 carbon atoms in a lineararrangement, e.g., —[(CH₂)_(n)]—, where n is an integer from 1 to 6,“(C₁-C₆)alkylene” includes methylene, ethylene, propylene, butylene,pentylene and hexylene. “(C₁-C₆)alkylene” also includes a divalentsaturated radical having from 1-6 carbon atoms in a branchedarrangement, for example: —[(CH₂CH₂CH₂CH₂CH(CH₃)]—,—[(CH₂CH₂CH₂CH₂C(CH₃)₂]—, —[(CH₂C(CH₃)₂CH(CH₃))]—, and the like. Whereindicated, alkylene is optionally and independently substituted with oneor more substituents independently selected from halo, (C₁-C₆)alkyl,—OH, ═O, (C₁-C₆)alkoxy, and (C₁-C₆)haloalkyl.

“Aryl” or “aromatic” means an aromatic monocyclic or polycyclic (e.g.bicyclic or tricyclic) carbocyclic ring system. In one embodiment,“aryl” is a 6-12 membered monocylic or bicyclic system. Aryl systemsinclude, but not limited to, phenyl, naphthyl, fluorenyl, indenyl,azulenyl, and anthracenyl. In certain preferred embodiments, “aryl” isphenyl.

“Carbocyclyl” means a cyclic group with only ring carbon atoms.“Carbocyclyl” includes 3-12 membered saturated or unsaturated aliphaticcyclic hydrocarbon rings or 6-12 membered aryl rings. A carbocyclylmoiety can be monocyclic, fused bicyclic, bridged bicyclic, spirobicyclic, or polycyclic.

Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclichydrocarbon rings or aromatic hydrocarbon rings having the specifiednumber of carbon atoms. Monocyclic carbocyclyls include cycloalkyl,cycloalkenyl, cycloalkynyl and phenyl.

A fused bicyclic carbocyclyl has two rings which have two adjacent ringatoms in common. The first ring is a monocyclic carbocyclyl and thesecond ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.

A bridged bicyclic carbocyclyl has two rings which have three or moreadjacent ring atoms in common. The first ring is a monocycliccarbocyclyl and the second ring is a monocyclic carbocyclyl or amonocyclic heterocyclyl. In some preferred embodiments, a bridgedbicyclic carbocylyl is adamantyl.

A spiro bicyclic carbocyclyl has two rings which have only one ring atomin common. The first ring is a monocyclic carbocyclyl and the secondring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.

Polycyclic carbocyclyls have more than two rings (e.g., three ringsresulting in a tricyclic ring system) and adjacent rings have at leastone ring atom in common. The first ring is a monocyclic carbocyclyl andthe remainder of the ring structures are monocyclic carbocyclyls ormonocyclic heterocyclyls. Polycyclic ring systems include fused, bridgedand spiro ring systems. A fused polycyclic ring system has at least tworings that have two adjacent ring atoms in common. A spiro polycyclicring system has at least two rings that have only one ring atom incommon. A bridged polycyclic ring system has at least two rings thathave three or more adjacent ring atoms in common.

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ring. Thus,“(C₃-C₇)cycloalkyl” means a hydrocarbon radical of a (3-7 membered)saturated aliphatic cyclic hydrocarbon ring. A C₃-C₇cycloalkyl includes,but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl.

“Cycloalkene” means an aliphatic cyclic hydrocarbon ring having one ormore double bonds in the ring.

“Cycloalkyne” means an aliphatic cyclic hydrocarbon ring having one ormore triple bonds in the ring.

“Hetero” refers to the replacement of at least one carbon atom member ina ring system with at least one heteroatom selected from N, S, and O.“Hetero” also refers to the replacement of at least one carbon atommember in a acyclic system. A hetero ring system or a hetero acyclicsystem may have 1, 2, 3 or 4 carbon atom members replaced by aheteroatom.

“Heterocyclyl” means a cyclic 4-12 membered saturated or unsaturatedaliphatic or aromatic ring containing 1, 2, 3, 4 or 5 heteroatomsindependently selected from N, O or S. When one heteroatom is S, it canbe optionally mono- or di-oxygenated (i.e. —S(O)— or —S(O)₂—). Theheterocyclyl can be monocyclic, fused bicyclic, bridged bicyclic, spirobicyclic or polycyclic.

“Saturated heterocyclyl” means an aliphatic heterocyclyl group withoutany degree of unsaturation (i.e. no double bond or triple bond). It canbe monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic orpolycyclic.

Examples of monocyclic saturated heterocyclyls include, but are notlimited to, azetidine, pyrrolidine, piperidine, piperazine, azepane,hexahydropyrimidine, tetrahydrofuran, tetrahydropyran, morpholine,thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-thiazine,tetrahydro-2H-1,2-thiazine 1,1-dioxide, isothiazolidine, isothiazolidine1,1-dioxide.

A fused bicyclic heterocyclyl has two rings which have two adjacent ringatoms in common. The first ring is a monocyclic heterocyclyl and thesecond ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl)or a monocyclic heterocyclyl. For example, the second ring is a(C₃-C₆)cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. Alternatively, the second ring is phenyl. Examples of fusedbicyclic heterocyclyls include, but are not limited to,octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline,2,3-dihydro-H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole,2,3-dihydrobenzo[d]thiazole, octahydrobenzo[d]oxazole,octahydro-1H-benzo[d]imidazole, octahydrobenzo[d]thiazole,octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3.1.0]hexane, and3-azabicyclo[3.2.0]heptane.

A spiro bicyclic heterocyclyl has two rings which have only one ringatom in common. The first ring is a monocyclic heterocyclyl and thesecond ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl)or a monocyclic heterocyclyl. For example, the second ring is a(C₃-C₆)cycloalkyl. Alternatively, the second ring is phenyl. Example ofspiro bicyclic heterocyclyl includes, but are not limited to,azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azaspiro[4.5]decane,8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecaneand 3,9-diazaspiro[5.5]undecane.

A bridged bicyclic heterocyclyl has two rings which have three or moreadjacent ring atoms in common. The first ring is a monocyclicheterocyclyl and the other ring is a monocyclic carbocycle (such as acycloalkyl or phenyl) or a monocyclic heterocyclyl. Examples of bridgedbicyclic heterocyclyls include, but are not limited to,azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane,azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane,6-azabicyclo[3.2.1]octane and azabicyclo[2.2.2]octane,2-azabicyclo[2.2.2]octane.

Polycyclic heterocyclyls have more than two rings, one of which is aheterocyclyl (e.g., three rings resulting in a tricyclic ring system)and adjacent rings having at least one ring atom in common. Polycyclicring systems include fused, bridged and spiro ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ringatoms in common. A spiro polycyclic ring system has at least two ringsthat have only one ring atom in common. A bridged polycyclic ring systemhas at least two rings that have three or more adjacent ring atoms incommon.

“Heteroaryl” or “heteroaromatic ring” means a 5-12 membered monovalentheteroaromatic monocyclic or bicyclic ring radical. A heteroarylcontains 1, 2, 3 or 4 heteroatoms independently selected from N, O, andS. Heteroaryls include, but are not limited to furan, oxazole,thiophene, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole,1,2,5-thiadiazole 1,1-dioxide, 1,2,5-thiadiazole 1-oxide,1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,5-triazine,imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine,pyridine-N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, andthiazole. Bicyclic heteroaryl rings include, but are not limited to,bicyclo[4.4.0] and bicyclo[4.3.0]fused ring systems such as indolizine,indole, isoindole, indazole, benzimidazole, benzthiazole, purine,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,quinoxaline, 1,8-naphthyridine, and pteridine.

In certain embodiments, where indicated, a group such as alkylene,adamantyl, naphthyl, or aryl may be optionally substituted. Exemplarysubstituents include halo, (C₁-C₆)alkyl, —OH, ═O, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy-(C₁-C₆)alkylene, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, and—C(O)—(C₁-C₆)alkyl.

In certain embodiments, where indicated, a phenyl group may have twoadjacent substituents that, taken together with the intervening atoms,form an optionally substituted heteroaryl, aryl, cycloalkyl, orheterocycloalkyl ring. By way of example, a phenyl group having twoadjacent substituents that, taken together with the intervening atoms,form a pyridinyl group can have the structure

or any positional isomer thereof. In another example, a phenyl grouphaving two adjacent substituents that, taken together with theintervening atoms, form a tetrahydropyranyl group can have the structure

or any positional isomer thereof.

“Halogen” and “halo” are interchangeably used herein and each refers tofluorine, chlorine, bromine, or iodine.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom.“(C₁-C₆)-alkoxy” includes methoxy, ethoxy, propoxy, butoxy, pentoxy andhexoxy.

Haloalkyl includes mono, poly, and perhaloalkyl groups where eachhalogen is independently selected from fluorine, chlorine, and bromine.

“Pharmaceutically acceptable carrier” means non-therapeutic componentsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention that, when appropriately administered toan animal or human, typically do not produce an adverse reaction, andthat are used as a vehicle for a drug substance (i.e. a compound of thepresent invention).

Pharmaceutically acceptable salts of the compounds of the presentinvention are also included. For example, an acid salt of a compound ofthe present invention containing an amine or other basic group can beobtained by reacting the compound with a suitable organic or inorganicacid, resulting in pharmaceutically acceptable anionic salt forms.Examples of anionic salts include the acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glyceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, triethiodide, and trifluoroacetate salts.

Salts of the compounds of the present invention containing a carboxylicacid or other acidic functional group can be prepared by reacting with asuitable base. Such a pharmaceutically acceptable salt may be made witha base which affords a pharmaceutically acceptable cation, whichincludes alkali metal salts (especially sodium and potassium), alkalineearth metal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as trimethylamine, triethylamine, morpholine,pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine,glucamine, N-methylglucamine, collidine, quinine, quinoline, and basicamino acids such as lysine and arginine.

tRNA Synthetase Inhibitor Compounds

In certain aspects, the invention provides a compound of formula (I):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   each of R¹, R², R³, R⁴, and R⁵ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(b) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R⁸, —O—CH₂—R⁸, and        —O—CH₂CH₂—O—R⁹;    -   or R¹ and R², R² and R³, R³ and R⁴, or R⁴ and R⁵, taken together        with the intervening atoms, form an optionally substituted aryl,        heteroaryl, cycloalkyl, or heterocycloalkyl group;    -   R⁶ is H or (C₁-C₆)alkyl;    -   R⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R⁸ is selected from —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl wherein the        heteroaryl is not 4-pyridinyl, benzimidazole or thiazole,        optionally substituted aryloxy(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,        (C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl,        heteroaryl(C₁-C₈)alkyl, (C₂-C₈)alkoxy, (C₃-C₈)hydroxyalkyl,        (C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₁-C₈)haloalkoxy(C₁-C₈)alkyl,        (C₁-C₈)thioalkoxy(C₁-C₈)alkyl, (CH₃SO₂)(C₁-C₈)alkyl, and        ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(b), independently for each occurrence, is selected from H,        optionally substituted (C₁-C₈)alkyl, optionally substituted        (C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally        substituted aryl, and optionally substituted aryl(C₁-C₈) alkyl;    -   further wherein:    -   at least one of R¹, R², R³, R⁴, and R⁵ is selected from        (C₃-C₈)alkyl, (C₂-C₈)hydroxyalkyl, (C₁-C₈)aminoalkyl, straight        chain (C₂-C₈)alkoxy, (C₁-C₈)haloalkoxy, (C₄-C₈)cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted aryloxy, (C₆-C₁₀)cycloalkoxy,        —OC(O)((C₁-C₈)alkyl), —NHC(O)(aryl), (H₃CSO₂)(C₁-C₈)alkylene,        optionally substituted (R^(b) ₂NSO₂)(C₁-C₈)alkylene,        di((C₁-C₈)alkyl)amino, —NH—CH₂—R⁸, —O—CH₂—R⁸, and        —O—CH₂CH₂—O—R⁹.

In certain embodiments, R⁶ is (C₁-C₆)alkyl, for example, methyl.

Alternatively, R⁶ may be H.

In certain embodiments, R⁷ is optionally substituted cyclohexyl orcyclohexenyl. In some preferred embodiments, R⁷ is optionallysubstituted cyclohexyl.

In certain embodiments, four of R¹, R², R³, R⁴, and R⁵ are H. Forexample, R², R³, R⁴, and R⁵ may each be H.

In certain embodiments, R¹ is selected from the group consisting of(C₃-C₈)alkyl, (C₂-C₈)hydroxyalkyl, (C₁-C₈)aminoalkyl, (C₄-C₈)cycloalkyl,aryl, heteroaryl, (CH₃SO₂)(C₁-C₈)alkyl, and di((C₁-C₈)alkyl)amino. Insome preferred embodiments, R¹ is selected from the group consisting ofaryl and heteroaryl.

In some embodiments, R¹ represents optionally substituted (R^(b)₂NSO₂)(C₁-C₈)alkylene.

Alternatively, R¹ may be selected from the group consisting of straightchain (C₂-C₈)alkoxy, (C₁-C₈)haloalkoxy, aryloxy, —OC(O)((C₁-C₈)alkyl),—O—CH₂—R⁸, and —O—CH₂CH₂—O—R⁹. For example, R¹ may be selected from thegroup consisting of straight chain (C₂-C₈)alkoxy, (C₁-C₈)haloalkoxy, andaryloxy. In other embodiments, R¹ is selected from the group consistingof —O—CH₂—R⁸ and —O—CH₂CH₂—O—R⁹. In some preferred embodiments, R¹ is—O—CH₂—R⁸ and R⁸ is optionally substituted heteroaryl wherein theheteroaryl is not 4-pyridinyl, benzimidazole or thiazole.

In further aspects, the invention provides a compound of formula (II′):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   X is O or S;    -   each of R¹⁰, R¹¹, R¹², and R¹³ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene,        (H₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino;    -   or R¹⁰ and R¹¹, R¹¹ and R¹², or R¹² and R¹³, taken together with        the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl group;    -   R¹⁴ is H or (C₁-C₆)alkyl;    -   R¹⁵ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;

represents a heterocyclic group substituted by oxo (═O) and optionallysubstituted by one or more additional substituents; and

-   -   n is an integer from 1-3.

In further aspects, the invention provides a compound of formula (II):

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   each of R¹⁰, R¹¹, R¹², and R¹³ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene,        (H₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino;    -   or R¹⁰ and R¹¹, R¹¹ and R¹², or R¹² and R¹³, taken together with        the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl group;    -   R¹⁴ is H or (C₁-C₆)alkyl;    -   R¹⁵ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;

represents a heterocyclic group substituted by oxo (═O) and optionallysubstituted by one or more additional substituents; and

-   -   n is an integer from 1-3.

In certain embodiments of the compounds of formula (II) and (II′), atleast three of R¹⁰, R¹¹, R¹², and R¹³ are H. For example, R¹⁰, R¹¹, R¹²,and R¹³ may each be H.

In certain embodiments, R¹⁴ is H. Alternatively, R¹⁴ may be(C₁-C₆)alkyl, e.g., methyl.

In certain embodiments, R¹⁵ is optionally substituted cyclohexyl orcyclohexenyl. In some preferred embodiments, R¹⁵ is optionallysubstituted cyclohexyl.

In certain embodiments,

represents optionally substituted oxazolidinone.

For example

may represent

Alternatively,

may represent

and R^(a) may represent (C₃-C₁₀)cycloalkyl or (C₁-C₈)alkyl.

In further aspects, the invention provides a compound of formula (III′):

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   each of R⁴⁰, R⁴¹, R⁴², and R⁴³ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene,        (H₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino;    -   or R⁴⁰ and R⁴¹, R⁴¹ and R⁴², or R⁴² and R⁴³, taken together with        the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl group;    -   R⁴⁴ is H or (C₁-C₆)alkyl;    -   R⁴⁵ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R^(c), independently for each occurrence, is selected from H,        (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₁-C₈)alkoxyl,        (C₁-C₈)hydroxyalkyl, (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, aryl, and aryl(C₁-C₈) alkyl;    -   R^(d), independently for each occurrence, is selected from H,        optionally substituted —C(O)alkyl, optionally substituted        —C(O)NH—(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, and        optionally substituted aryl(C₁-C₈) alkyl, or    -   two R^(d) are taken together with the nitrogen atom to which        they are attached to form an optionally substituted 5-6-membered        heterocyclyl; and    -   m is an integer from 1-3.

In other aspects, the invention provides a compound of formula (III):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   each of R⁴⁰, R⁴¹, R⁴², and R⁴³ is independently selected from H,        OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene,        (H₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino;    -   or R⁴⁰ and R⁴¹, R⁴¹ and R⁴², or R⁴² and R⁴³, taken together with        the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl group;    -   R⁴⁴ is H or (C₁-C₆)alkyl;    -   R⁴⁵ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R^(c), independently for each occurrence, is selected from H,        (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₁-C₈)alkoxyl,        (C₁-C₈)hydroxyalkyl, (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, aryl, and aryl(C₁-C₈) alkyl;    -   R^(d), independently for each occurrence, is selected from H,        optionally substituted (C₁-C₈)alkyl, optionally substituted        (C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally        substituted aryl, and optionally substituted aryl(C₁-C₈) alkyl;        and    -   m is an integer from 1-3.

In certain embodiments of the compounds of formula (III), at least threeof R⁴⁰, R⁴¹, R⁴², and R⁴³ are H. For example, R⁴⁰, R⁴¹, R⁴², and R⁴³ mayeach be H.

In certain embodiments, R⁴⁴ is H. Alternatively, R⁴⁴ may be(C₁-C₆)alkyl, e.g., methyl.

In certain embodiments, R⁴⁵ is optionally substituted cyclohexyl orcyclohexenyl. In some preferred embodiments, R⁴⁵ is optionallysubstituted cyclohexyl.

In certain embodiments, R^(c) is H.

In certain embodiments, R^(d), independently for each occurrence, isselected from H and (C₁-C₈)alkyl, preferably H. In other embodiments,each R^(d) is methyl. In certain embodiments, one R^(d) is methyl orethyl and the other R^(d) is H.

In certain embodiments, one R^(d) is optionally substituted —C(O)alkyl,such as —C(O)CH(NH₂)CH₂CHMe₂. In other embodiments, one R^(d) is—C(O)NH—(C₃-C₁₀)cycloalkyl, such as —C(O)NH-cyclohexyl, optionallysubstituted with methyl.

In certain embodiments, one R^(d) is optionally substituted(C₁-C₈)alkyl, such as —CH₂CH(OH)CH₂OH. In other embodiments, one R^(d)is —CH₂CH(OH)CH₂OH and the other R^(d) is methyl. In certainembodiments, one R^(d) is —CH₂C(O)NHCH₂COOH. In some embodiments, oneR^(d) is —CH₂CH₂OMe. In certain embodiments, one R^(d) is —CH₂COOH. Inother embodiments, one R^(d) is —CH(Me)COOH. In other embodiments, oneR^(d) is —CH₂-heterocyclyl, such as —CH₂-furanyl.

In certain embodiments, one R^(d) is optionally substituted cycloalkyl,such as 3-COOHcyclobutyl. In other embodiments, one R^(d) is optionallysubstituted aryl, such as 3-(B(OH₃))-phenyl. In certain embodiments, oneR^(d) is optionally substituted heterocyclyl, such asN-methylpiperidinyl.

In certain embodiments, both R^(d) are taken together with the nitrogenatom to which they are attached to form an optionally substituted5-6-membered heterocyclyl, such as an N-methylpiperizinyl.

In some aspects, the invention provides a compound, or apharmaceutically acceptable salt thereof, selected from Table 1:

TABLE 1 Compounds of the Invention

Further compounds of the invention include, but are not limited to thefollowing compounds in Table 2.

TABLE 2

Pharmaceutical Compositions

In certain aspects, the invention also provides a pharmaceuticalcomposition comprising a compound of the invention (e.g., a compound offormula (I)), in combination with a pharmaceutically acceptable carrier.

The invention further includes the process for making the compositioncomprising mixing one or more of the present compounds and an optionalpharmaceutically acceptable carrier; and includes those compositionsresulting from such a process, which process includes conventionalpharmaceutical techniques.

The compositions of the invention include ocular, oral, nasal,transdermal, topical with or without occlusion, intravenous (both bolusand infusion), inhalable, and injection (intraperitoneally,subcutaneously, intramuscularly, intralesionally, or parenterally)formulations. The composition may be in a dosage unit such as a tablet,pill, capsule, powder, granule, liposome, ion exchange resin, sterileocular solution, or ocular delivery device (such as a contact lens andthe like facilitating immediate release, timed release, or sustainedrelease), parenteral solution or suspension, metered aerosol or liquidspray, drop, ampoule, auto-injector device, or suppository; foradministration ocularly, orally, intranasally, sublingually,parenterally, or rectally, or by inhalation or insufflation.

Compositions of the invention suitable for oral administration includesolid forms such as pills, tablets, caplets, capsules (each includingimmediate release, timed release, and sustained release formulations),granules and powders; and, liquid forms such as solutions, syrups,elixirs, emulsions, and suspensions. Forms useful for ocularadministration include sterile solutions or ocular delivery devices.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

The compositions of the invention may be administered in a form suitablefor once-weekly or once-monthly administration. For example, aninsoluble salt of the active compound may be adapted to provide a depotpreparation for intramuscular injection (e.g., a decanoate salt) or toprovide a solution for ophthalmic administration.

The dosage form containing the composition of the invention contains aneffective amount of the active ingredient necessary to provide atherapeutic effect. The composition may contain from about 5,000 mg toabout 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of acompound of the invention or salt form thereof and may be constitutedinto any form suitable for the selected mode of administration. Thecomposition may be administered about 1 to about 5 times per day. Dailyadministration or post-periodic dosing may be employed.

For oral administration, the composition is preferably in the form of atablet or capsule containing, e.g., 500 to 0.5 milligrams of the activecompound. Dosages will vary depending on factors associated with theparticular patient being treated (e.g., age, weight, diet, and time ofadministration), the severity of the condition being treated, thecompound being employed, the mode of administration, and the strength ofthe preparation.

The oral composition is preferably formulated as a homogeneouscomposition, wherein the active ingredient is dispersed evenlythroughout the mixture, which may be readily subdivided into dosageunits containing equal amounts of a compound of the invention.Preferably, the compositions are prepared by mixing a compound of theinvention (or pharmaceutically acceptable salt thereof) with one or moreoptionally present pharmaceutical carriers (such as a starch, sugar,diluent, granulating agent, lubricant, glidant, binding agent, anddisintegrating agent), one or more optionally present inertpharmaceutical excipients (such as water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents, and syrup), one ormore optionally present conventional tableting ingredients (such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesiumstearate, dicalcium phosphate, and any of a variety of gums), and anoptional diluent (such as water).

Binder agents include starch, gelatin, natural sugars (e.g., glucose andbeta-lactose), corn sweeteners and natural and synthetic gums (e.g.,acacia and tragacanth). Disintegrating agents include starch, methylcellulose, agar, and bentonite.

Tablets and capsules represent an advantageous oral dosage unit form.Tablets may be sugarcoated or film-coated using standard techniques.Tablets may also be coated or otherwise compounded to provide aprolonged, control-release therapeutic effect. The dosage form maycomprise an inner dosage and an outer dosage component, wherein theouter component is in the form of an envelope over the inner component.The two components may further be separated by a layer which resistsdisintegration in the stomach (such as an enteric layer) and permits theinner component to pass intact into the duodenum or a layer which delaysor sustains release. A variety of enteric and non-enteric layer orcoating materials (such as polymeric acids, shellacs, acetyl alcohol,and cellulose acetate or combinations thereof) may be used.

Compounds of the invention may also be administered via a slow releasecomposition; wherein the composition includes a compound of theinvention and a biodegradable slow release carrier (e.g., a polymericcarrier) or a pharmaceutically acceptable non-biodegradable slow releasecarrier (e.g., an ion exchange carrier).

Biodegradable and non-biodegradable slow release carriers are well knownin the art. Biodegradable carriers are used to form particles ormatrices which retain an active agent(s) and which slowlydegrade/dissolve in a suitable environment (e.g., aqueous, acidic, basicand the like) to release the agent. Such particles degrade/dissolve inbody fluids to release the active compound(s) therein. The particles arepreferably nanoparticles or nanoemulsions (e.g., in the range of about 1to 500 nm in diameter, preferably about 50-200 nm in diameter, and mostpreferably about 100 nm in diameter). In a process for preparing a slowrelease composition, a slow release carrier and a compound of theinvention are first dissolved or dispersed in an organic solvent. Theresulting mixture is added into an aqueous solution containing anoptional surface-active agent(s) to produce an emulsion. The organicsolvent is then evaporated from the emulsion to provide a colloidalsuspension of particles containing the slow release carrier and thecompound of the invention.

The compounds disclosed herein may be incorporated for administrationorally or by injection in a liquid form such as aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, flavored emulsionswith edible oils such as cottonseed oil, sesame oil, coconut oil orpeanut oil and the like, or in elixirs or similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions, include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also includesynthetic and natural gums. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations, whichgenerally contain suitable preservatives, are employed when intravenousadministration is desired.

The compounds may be administered parenterally via injection. Aparenteral formulation may consist of the active ingredient dissolved inor mixed with an appropriate inert liquid carrier. Acceptable liquidcarriers usually comprise aqueous solvents and other optionalingredients for aiding solubility or preservation. Such aqueous solventsinclude sterile water, Ringer's solution, or an isotonic aqueous salinesolution. Other optional ingredients include vegetable oils (such aspeanut oil, cottonseed oil, and sesame oil), and organic solvents (suchas solketal, glycerol, and formyl). A sterile, non-volatile oil may beemployed as a solvent or suspending agent. The parenteral formulation isprepared by dissolving or suspending the active ingredient in the liquidcarrier whereby the final dosage unit contains from 0.005 to 10% byweight of the active ingredient. Other additives include preservatives,isotonizers, solubilizers, stabilizers, and pain-soothing agents.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed.

Compounds of the invention may be administered intranasally using asuitable intranasal vehicle.

In other embodiments, the compounds of this invention may beadministered directly to the lungs by inhalation.

Compounds of the invention may also be administered topically orenhanced by using a suitable topical transdermal vehicle or atransdermal patch.

For ocular administration, the composition is preferably in the form ofan ophthalmic composition. The ophthalmic compositions are preferablyformulated as eye-drop formulations and filled in appropriate containersto facilitate administration to the eye, for example a dropper fittedwith a suitable pipette. Preferably, the compositions are sterile andaqueous based, using purified water. In addition to the compound of theinvention, an ophthalmic composition may contain one or more of: a) asurfactant such as a polyoxyethylene fatty acid ester; b) a thickeningagents such as cellulose, cellulose derivatives, carboxyvinyl polymers,polyvinyl polymers, and polyvinylpyrrolidones, typically at aconcentration n the range of about 0.05 to about 5.0% (wt/vol); c) (asan alternative to or in addition to storing the composition in acontainer containing nitrogen and optionally including a free oxygenabsorber such as Fe), an anti-oxidant such as butylated hydroxyanisol,ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at aconcentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at aconcentration of about 0.01 to 0.5% (wt/vol); and e) other excipientssuch as an isotonic agent, buffer, preservative, and/or pH-controllingagent. The pH of the ophthalmic composition is desirably within therange of 4 to 8.

In certain embodiments, the pharmaceutical composition of the inventionfurther comprises one or more additional agents, such as a secondantibacterial agent. The other agent may be ay agent that is capable oftreating, suppressing, or preventing a bacterial infection. For example,the other therapeutic agent may be an antibacterial compound.Alternatively, the other therapeutic agent may be any agent of benefitto a patient when administered in combination with the tRNA synthetaseinhibitor compound in this invention.

In certain embodiments, the second antibacterial agent in thepharmaceutical composition of the invention is a tRNA synthetaseinhibitor. Exemplary tRNA synthetase inhibitors include oxaborolecompounds such as AN3365.

Methods of Treatment

In certain aspects, the invention provides methods of treating abacterial infection in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of theinvention, i.e., a compound of formula (I), formula (II), formula (II′),formula (III), formula (III′), or a compound pictured in Table 1, or apharmaceutical composition comprising the compound.

The invention further provides methods of treating a bacterial infectionin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (IV′):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   each of R²¹, R²², R²³, R²⁴, and R²⁵ is independently selected        from H, OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂, optionally        substituted —S—(C₁-C₆)alkyl; tri((C₁-C₈)alkyl)silyl, optionally        substituted (C₁-C₈)alkyl, optionally substituted (C₁-C₈)alkoxy,        optionally substituted (C₁-C₈)aminoalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₁-C₈)haloalkyl,        optionally substituted (C₁-C₈)haloalkoxy, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        aryloxy, optionally substituted arylalkoxy, optionally        substituted heteroaryloxy, optionally substituted        heteroarylalkoxy, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted (C₃-C₁₀)cycloalkoxy, optionally        substituted (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(e) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R²⁸, —O—CH₂—R²⁸, and        —O—CH₂CH₂—O—R²⁹;    -   or R²¹ and R²², R²² and R²³, R²³ and R²⁴, or R²⁴ and R²⁵, taken        together with the intervening atoms, form an optionally        substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        group;    -   R²⁶ is H or (C₁-C₆)alkyl;    -   R²⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R²⁸ is selected from H, —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl, optionally        substituted aryl, optionally substituted aryloxy(C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, (C₂-C₉)heterocycloalkyl,        (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl, heteroaryl(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, (C₂-C₈)hydroxyalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        (C₁-C₈)haloalkoxy(C₁-C₈)alkyl, (C₁-C₈)thioalkoxy(C₁-C₈)alkyl,        (CH₃SO₂)(C₁-C₈)alkyl, and ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R²⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(e), independently for each occurrence, is selected from H,        optionally substituted —C(O)(C₁-C₈)alkyl, optionally substituted        —C(O)NH—(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, and        optionally substituted aryl(C₁-C₈) alkyl, or    -   two R^(e) are taken together with the nitrogen atom to which        they are attached to form a 5-6-membered heterocyclyl;    -   further wherein:

if R²⁶ is (C₁-C₆)alkyl and R²⁷ is (C₆)cycloalkyl, then R²¹ and R²⁵ arenot OH, —OC(O)((C₁-C₈)alkyl), optionally substituted (C₁-C₈)alkoxy,optionally substituted (C₁-C₈)haloalkoxy, optionally substitutedaryloxy, optionally substituted arylalkoxy, optionally substitutedheteroaryloxy, optionally substituted heteroarylalkoxy, optionallysubstituted (C₃-C₁₀)cycloalkoxy, optionally substituted(C₂-C₉)heterocycloalkoxy, —O—CH₂—R²⁸, or —O—CH₂CH₂—O—R²⁹.

The invention further provides methods of treating a bacterial infectionin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (IV):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   each of R²¹, R²², R²³, R²⁴, and R²⁵ is independently selected        from H, OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(e) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R²⁸, —O—CH₂—R²⁸, and        —O—CH₂CH₂—O—R²⁹;    -   or R²¹ and R²², R²² and R²³, R²³ and R²⁴, or R²⁴ and R²⁵, taken        together with the intervening atoms, form an optionally        substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        group;    -   R²⁶ is H or (C₁-C₆)alkyl;    -   R²⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R²⁸ is selected from —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl, optionally        substituted aryl, optionally substituted aryloxy(C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, (C₂-C₉)heterocycloalkyl,        (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl, heteroaryl(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, (C₂-C₈)hydroxyalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        (C₁-C₈)haloalkoxy(C₁-C₈)alkyl, (C₁-C₈)thioalkoxy(C₁-C₈)alkyl,        (CH₃SO₂)(C₁-C₈)alkyl, and ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R²⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(e), independently for each occurrence, is selected from H,        optionally substituted (C₁-C₈)alkyl, optionally substituted        (C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally        substituted aryl, and optionally substituted aryl(C₁-C₈) alkyl;    -   further wherein:

if R²⁶ is (C₁-C₆)alkyl and R²⁷ is (C₆)cycloalkyl, then R²¹ and R²⁵ arenot OH, —OC(O)((C₁-C₈)alkyl), optionally substituted (C₁-C₈)alkoxy,optionally substituted (C₁-C₈)haloalkoxy, optionally substitutedaryloxy, optionally substituted arylalkoxy, optionally substitutedheteroaryloxy, optionally substituted heteroarylalkoxy, optionallysubstituted (C₃-C₁₀)cycloalkoxy, optionally substituted(C₂-C₉)heterocycloalkoxy, —O—CH₂—R²⁸, or —O—CH₂CH₂—O—R²⁹.

In certain embodiments of the methods of the invention, the bacterialinfection is caused by Gram-negative bacteria.

Exemplary Gram-negative bacteria used with the methods of the inventioninclude Acidaminococcus spp (e.g. A. fermentans, A. intestin),Acinetobacter spp (e.g. A. baumannii, A. calcoaceticus, A. gyllenbergii,A. haemolyticus, A. junii, A. lwoffii, A. nosocomialis, A. parvus, A.pittii, A. schindleri, A. seifertii, A. soli, A. ursingii, A.variabilis), Aggregatibacter spp (A. actinomycetemcomitans, A.aphrophilus, A. segnis), Agrobacterium tumefaciens, Anaerobiospirillumaka Anaerobiospirillum thomasii, Arcobacter spp (e.g. A. skirrowii, A.butzleri, A. cryaerophilus), Bacteroides spp, (B. fragilis, B.ureolyticus, B. melaninogenicus), Bartonella spp (e.g. B. japonica, B.koehlerae, B. taylorii, B. alsatica, B. ancashensis, B. bacilliformis,B. capreoli, B. clarridgeiae, B. doshiae, B. elizabethae, B. grahamii,B. henselae, B. peromysci, B. quintana, B. rochalimae, B.schoenbuchensis, B. talpae, B. tamiae, B. tribocorum, B. vinsonii, B.washoensis), Bordetella spp (e.g. B. ansorpii, B. avium, B.bronchiseptica, B. hinzii, B. holmesii, B. parapertussis, B. pertussis,B. trematum), Borrelia spp. (e.g. B. burgdorferi, B. afzelii, B.garinii, B. andersonii, B. anserine, B. bissettii, B. carolinensis, B.hermsii, B. kurtenbachii, B. lusitaniae, B. miyamotoi, B. parkeri, B.recurrentis, B. sinica, B. spielmanii, B. turicatae), Brachyspira spp(e.g. B. aalborgi, B. pilosicoli, B. hyodysenteriae), Bradyrhizobium spp(e.g. B. japonicum, B. enterica), Burkholderia spp (e.g. B. mallei, B.pseudomallei, B. cepacia, B. dolosa), Campylobacter spp. (e.g. C.jejuni, C. coli, C. upsaliensis, C. fetus, C. lari, C. hyointestinalis,C. rectus), Cardiobacterium spp. (e.g. C. hominis, C. valvarum),Christensenella spp (e.g. C. minuta, C. massiliensis, C. timonensis),Citrobacter spp. (e.g. C. amalonaticus, C. braakii, C. koseri, C.sedlakii), Coxiella burnetii, Cytophaga spp. (e.g. C. columnaris, C.johnsonae, C. psychrophila), Dialister spp (e.g. D. pneumosintes),Eikenella corrodens, Enterobacter spp (e.g. E. cloacae, E. aerogenes, E.cancerogenus aka E. taylorae, E. cowanii), Escherichia spp (e.g. E.coli, E. fergusonii, E. hermannii, E. albertii, E. vulneris), Ewingellaamericana, Flavobacterium spp (e.g. F. psychrophilum, F. columnare, F.branchiophilum), Francisella spp. (e.g. F. novicida, F. tularensis, F.piscicida, F. philomiragia), Fusobacterium spp (e.g F. necrophorum, F.nucleatum, F. polymorphum), Haemophilus spp (e.g H. felis, H.haemolyticus, H. influenzae, H. parainfluenzae, H. pittmaniae, H.ducreyi), Helicobacter spp (e.g. H. pylori, H. bilis, H. canadensis, H.canis, H. cinaedi), Kingella spp (e.g. Kingella kingae aka Moraxellakingae, K. indologenes, K. denitrificans, K. oralis), Klebsiella spp(e.g. K. pneumoniae, K. granulomatis, K. oxytoca, K. michiganensis, K.quasipneumoniae, K. variicola), Kluyvera spp (e.g. K. intermedia, K.ascorbate, K. cryocrescens, K. intestine, K. georgiana), Legionella spp(e.g Legionella clemsonensis, Legionella pneumophila, L. wadsworthii, L.waltersii, L. anisa, L. birminghamensis, L. bozemanae, L. cardiaca, L.cherrii, L. cincinnatiensis, L. dumoffli, L. feeleii, L. gormanii, L.hackeliae, L. jordanis, L. lansingensis, L. longbeachae, L.oakridgensis, L. micdadei, L. rubrilucens, L. sainthelensi, L. steelei,L. tucsonensis), Leptonema illini, Leptotrichia spp (e.g. L. buccalis,L. amnionii, L. trevesanii, L. goodfellowii), Methylobacterium spp (e.g.M. fujisawaense, M. mesophilicum, M. thiocyanatum, M. aminovorans, M.lusitanum, M. radiotolerans), Moraxella spp. (e.g. M. lacunata akaMorax-Axenfeld diplobacilli, M. bovis, M. osloensis, M. atlantae, M.boevrei, M. bovoculi, M. canis, M. caprae, M. catarrhalis, M. caviae, M.cuniculi, M. equi, M. lincolnii, M. nonliquefaciens, M. oblonga, M.osloensis, M. pluranimalium, M. porci, M. saccharolytica), Morganellamorganii, Mycoplasma spp. (e.g M. spumans, M. adleri, M agalactiae, M.agassizii, M. alligatoris, M. amphoriforme, M. bovis, M. buccale, M.capricolum, M. faucium, M. fermentans, M. gallisepticum, M. genitalium,M. haemofelis, M. haemomuris, M. hominis, M. hyopneumoniae, M.hyorhinis, M. lipophilum, M. mobile, M. mycoides, M. orale, M.ovipneumoniae, M. penetrans, M. pirum, M. pneumoniae, M, primatum, M.salivarium, M. spermatophilum, M. synoviae), Neisseria spp. (e.g. N.gonorrhoeae, N. meningitides, N. cinerea, N. polysaccharea, N. sicca),Proteus spp. (e.g. P. mirabilis, P. penneri, P. hauseri, P. myxofaciens,P. vulgaris), Pseudomonas spp. (e.g. P. aeruginosa, P. oryzihabitans, P.luteola, P. floridensis, P. syringae, P. anguilliseptica, P.argentinensis, P. flavescens, P. mendocina, P. asplenii, P. corrugate,P. fragi, P. lundensis, P. taetrolens, P. azotoformans, P. blatchfordae,P. brassicacearum, P. fluorescens, P. marginalis, P. mediterranea, P.mucidolens, P. panacis, P. tolaasii, P. cremoricolorata, P. entomophila,P. monteilii, P. plecoglossicida, P. stutzeri, P. amygdali, P.avellanae, P. caricapapayae, P. cichorii, P. coronafaciens, P.ficuserectae, P. helianthin, P. meiae, P. savastanoi, P. tomato, P.viridiflava, P. asplenii, P. cannabina, P. costantinii, P. fuscovaginae,P. otitidis, P. palleroniana, P. perolens, P. reptilivora, P. salomonii,P. septica, P. simiae, P. suis, P. tremae, P. turbinellae),Pseudoxanthomonas spp. (e.g. P. broegbernensis, P. japonensis, P.mexicana), Rickettsia spp. (e.g. R. rickettsii, R. asiatica, R.australis, R. conorii, R. felis, R. heilongjiangensis, R. helvetica, R.honei, R. japonica, R. massiliae, R. monacensis, R. parkeri, R.peacockii, R. prowazekii, R. akari, R. africae, R. sibirica, R. typhi),Rouxiella chamberiensis, Salmonella spp (e.g. S. bongori, S. enterica),Serratia spp. (e.g. S. marcescens, S. plymuthica, S. liquefaciens, S.rubidaea, S. odorifera, S. fonticola), Shigella spp. (e.g. S.dysenteriae, S. flexneri, S. boydii, S. sonnei), Solobacterium moorei,Sphingomonas spp (S. gei, S. paucimobilis, S. koreensis), Spirochaetaspp, Stenotrophomonas spp (e.g. S. nitritireducens, S. maltophilia),Treponema spp. (e.g. T. pallidum, T. carateum, T. denticola, T.lecithinolyticum, T. maltophilum, T. socranskii, T. vincentii), Vibriospp (e.g. V. adaptatus, V. azasii, V. campbellii, V. cholera, V.alginolyticus, V. anguillarum, V. campbellii, V. fluvialis, V.furnissii, V. harveyi, V. lentus, V. mimicus, V. ordalii, V.parahaemolyticus, V. pectenicida, V. tapetis, V. tubiashii, V.vulnificus), Wolbachia spp., and Yersinia spp. (e.g. Y. aldovae, Y.bercovieri, Y. enterocolitica, Y. frederiksenii, Y. pestis, Y.pseudotuberculosis, Y. ruckeri).

In other embodiments, the bacterial infection treated by the methods ofthe invention is caused by Mycobacterium kansasii, Mycobacteriummarinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacteriumszulgai, Mycobacterium gordonae; Mycobacterium avium complex,Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium malmoense,Mycobacterium terrae complex, Mycobacterium haemophilum, Mycobacteriumgenavense, Mycobacterium abscessus complex, Mycobacterium chelonae,Mycobacterium fortuitum complex, or Mycobacterium peregrinum.

In further embodiments, the bacterial infection treated by the methodsof the invention is caused by a Nocardia species selected from N.concava, N. cyriacigeorgica, N. donostiensis, N. elegans, N. exalbida,N. farcinica, N. harenae, N. higoensis, N. ignorata, N. inohanensis, N.jinanensis, N. kroppenstedtii, N. kruczakiae, N. mexicana, N. mikamii,N. neocaledoniensis, N. niigatensis, N. ninae, N. niwae, N. nova, N.otitidiscaviarum, N. paucivorans, N. pneumoniae, N. pseudobrasiliensis,N. puris, N. shinanonensis, N. sienata, N. takedensis, N. terpenica, N.testaceae, N. thailandica, N. transvalensis, N. vermiculata, N.veterana, N. vulneris, N. wallacei, and N. yamanashiensis.

In further embodiments, the bacterial infection treated by the methodsof the invention is caused by a Actinomyces species selected from A.israelii, A. viscosus, A. meyeri, A. naeslundii, A. odontolyticus, A.gerencseriae, A. neuii, A. turicensis, and A. radingae.

When administered in combination with a second antibacterial agent, thecompounds of the invention may be effective to overcome bacterialresistance to the second antibacterial agent. Thus, in certainembodiments, the method of treating a bacterial infection provided bythe invention further comprises administering to the subject a secondantibacterial agent. In some embodiments, the second antibacterial agentis a tRNA synthtase inhibitor such as AN3365.

In certain embodiments, the invention provides methods of treatingtuberculosis, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of the invention, i.e., acompound of formula (I), formula (II), formula (II′), formula (III),formula (III′), or a compound pictured in Table 1, or a pharmaceuticalcomposition comprising the compound.

The invention further provides methods of treating tuberculosis,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (V′):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   each of R³¹, R³², R³³, R³⁴, and R³⁵ is independently selected        from H, OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂, optionally        substituted —S—(C₁-C₆)alkyl; tri((C₁-C₈)alkyl)silyl, optionally        substituted (C₁-C₈)alkyl, optionally substituted (C₁-C₈)alkoxy,        optionally substituted (C₁-C₈)aminoalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₁-C₈)haloalkyl,        optionally substituted (C₁-C₈)haloalkoxy, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        aryloxy, optionally substituted arylalkoxy, optionally        substituted heteroaryloxy, optionally substituted        heteroarylalkoxy, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted (C₃-C₁₀)cycloalkoxy, optionally        substituted (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(f) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R³⁸, —O—CH₂—R³⁸, and        —O—CH₂CH₂—O—R³⁹;    -   or R³¹ and R³², R³² and R³³, R³³ and R³⁴, or R³⁴ and R³⁵, taken        together with the intervening atoms, form an optionally        substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        group;    -   R³⁶ is H or (C₁-C₆)alkyl;    -   R³⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R³⁸ is selected from H, —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl, optionally        substituted aryl, optionally substituted aryloxy(C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, (C₂-C₉)heterocycloalkyl,        (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl, heteroaryl(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, (C₂-C₈)hydroxyalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        (C₁-C₈)haloalkoxy(C₁-C₈)alkyl, (C₁-C₈)thioalkoxy(C₁-C₈)alkyl,        (CH₃SO₂)(C₁-C₈)alkyl, and ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R³⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(f), independently for each occurrence, is selected from H,        optionally substituted —C(O)(C₁-C₈)alkyl, optionally substituted        —C(O)NH—(C₃-C₁₀)cycloalkyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)hydroxyalkyl, optionally substituted (C₃-C₁₀)cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, and        optionally substituted aryl(C₁-C₈) alkyl, or    -   two R^(f) are taken together with the nitrogen atom to which        they are attached to form a 5-6-membered heterocyclyl.

The invention further provides methods of treating tuberculosis,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (V):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein:    -   each of R³¹, R³², R³³, R³⁴, and R³⁵ is independently selected        from H, OH, —NH₂, halide, sulfonamido, (C₁-C₆)alkylsulfonyl,        —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally        substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,        tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl,        optionally substituted (C₁-C₈)alkoxy, optionally substituted        (C₁-C₈)aminoalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₁-C₈)haloalkyl, optionally substituted        (C₁-C₈)haloalkoxy, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted aryloxy,        optionally substituted arylalkoxy, optionally substituted        heteroaryloxy, optionally substituted heteroarylalkoxy,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkoxy, optionally substituted        (C₂-C₉)heterocycloalkyl, optionally substituted        (C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionally        substituted (R^(f) ₂NSO₂)(C₁-C₈)alkylene, optionally substituted        di((C₁-C₈)alkyl)amino, —NH—CH₂—R³⁸, —O—CH₂—R³⁸, and        —O—CH₂CH₂—O—R³⁹;    -   or R³¹ and R³², R³² and R³³, R³³ and R³⁴, or R³⁴ and R³⁵, taken        together with the intervening atoms, form an aryl, heteroaryl,        cycloalkyl, or heterocycloalkyl group;    -   R³⁶ is H or (C₁-C₆)alkyl;    -   R³⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or        (C₃-C₁₀)cycloalkenyl;    -   R³⁸ is selected from —C(O)((C₂-C₉)heterocycloalkyl),        —C(O)NH((C₁-C₈)alkyl), —C(O)NH(aryl(C₁-C₈)alkyl),        —C(O)NH((C₃-C₈)cycloalkyl),        —C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl),        —C(O)N(CH₃)((C₃-C₈)cycloalkyl), —C(O)N(CH₃)(aryl(C₁-C₈)alkyl),        —C(O)NHC(O)NH((C₃-C₈)cycloalkyl), —C(O)NHC(O)NH((C₁-C₈)alkyl),        —C(O)NHC(O)NH₂, optionally substituted heteroaryl, optionally        substituted aryl, optionally substituted aryloxy(C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, (C₂-C₉)heterocycloalkyl,        (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl, heteroaryl(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, (C₂-C₈)hydroxyalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        (C₁-C₈)haloalkoxy(C₁-C₈)alkyl, (C₁-C₈)thioalkoxy(C₁-C₈)alkyl,        (CH₃SO₂)(C₁-C₈)alkyl, and ((C₁-C₈)alkylC(O))(C₁-C₈)alkyl;    -   R³⁹ is selected from (C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl,        (C₁-C₈)hydroxyalkyl, (C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,        and optionally substituted aryl; and    -   R^(f), independently for each occurrence, is selected from H,        optionally substituted (C₁-C₈)alkyl, optionally substituted        (C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl,        optionally substituted (C₃-C₁₀)cycloalkyl, optionally        substituted (C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally        substituted aryl, and optionally substituted aryl(C₁-C₈) alkyl.

In some embodiments, at least four of R³¹, R³², R³³, R³⁴, and R³⁵ are H.For example, R³², R³³, R³⁴, and R³⁵ may each be H.

In certain embodiments, R³¹ and R³², taken together with the interveningatoms, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group,preferably a heteroaryl group.

In certain embodiments, R³¹ is selected from the group consisting of—OH, —OC(O)((C₁-C₈)alkyl), optionally substituted (C₁-C₈)alkoxy,optionally substituted (C₁-C₈)haloalkoxy, optionally substitutedaryloxy, optionally substituted arylalkoxy, optionally substitutedheteroaryloxy, optionally substituted heteroarylalkoxy, optionallysubstituted (C₃-C₁₀)cycloalkoxy, optionally substituted(C₂-C₉)heterocycloalkoxy, —O—CH₂—R³⁸, and —O—CH₂CH₂—O—R³⁹.

In certain embodiments, R³⁶ is (C₁-C₆)alkyl, e.g., methyl.Alternatively, R³⁶ may be H.

In certain embodiments, R³⁷ is optionally substituted cyclohexyl orcyclohexenyl, preferably optionally substituted cyclohexyl.

In certain embodiments, the subject is a mammal, e.g., a human.

EXAMPLES Example 1: General Synthetic Procedures 1

Certain compounds of the invention are synthesized according toSynthetic Scheme 1:

Synthetic Scheme 1

For example, N-benzyl-1-cyclohexylbutan-2-amine (B164) was synthesizedas follows:

Step 1: Preparation of 2

To a solution of 1 (1.5 g, 11.895 mmol, 1.0 eq) in THF (24 mL, c=0.5)was added dropwise ethylmagnesium bromide (24 mL, 1M in THF, 23.79 mmol,2.0 eq) at 0° C. under nitrogen. After 0.5 h at 0° C., the reactionmixture was added to aq. HCl (2N, 40 mL) at 0° C. The solution wasextracted with EA (3×30 mL). The combined organic phases were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography to give the desiredproduct 2 (1.313 g, yield=71%) as a yellow oil.

Step 2: Preparation of 3

To a solution of 2 (1.25 g, 8.005 mmol, 1 eq) and triethylamine (4.05 g,40.026 mmol, 5.0 eq) in DCM (32 mL, c=0.25) was added dropwise MsCl (2.3g, 20.013 mmol, 2.5 eq) at 0° C. After 20 min at 0° C., the reactionmixture was washed with aq.HCl (2N, 2×30 mL) and extracted with EA (3×30mL). The combined organic phases were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bycolumn chromatography to give the desired product 3 (1.511 g, yield=81%)as a yellow oil.

Step 3: Preparation of B164

To a solution of 3 (100 mg, 0.427 mmol, 1 eq) in CH₃CN (2 mL, c=0.2) wasadded BnNH₂ (275 mg, 2.562 mmol, 6 eq) and KI (35 mg, 0.213 mmol, 0.5eq) and the reaction mixture was refluxed at 80° C. for 1.5 h. Aftercompletion, the suspension was concentrated in vacuum and the residuewas purified by column chromatography to give the desired product B164(30.8 mg, yield=29%) as a yellow oil. ¹H NMR (400 MHz, DMSO): δ7.34-7.20 (m, 5H), 3.74-3.64 (m, 2H), 2.50-2.45 (m, 1H), 1.62-1.10 (m,15H), 0.89-0.75 (m, 3H). Mass: m/z=246 [M+H]⁺

The following compounds were synthesized via similar routes:

Compound Name, ID Structure ¹H NMR (400 MHz), MS B165: N-benzyl-1-cyclohexylpentan-2- amine

¹H NMR (DMSO): δ 7.35-7.28 (m, 4H), 7.23-7.21 (m, 1H), 3.73-3.71 (m,2H), 2.52-2.50 (m, 1H), 1.64-0.81 (m, 20H); Mass: m/z = 260 [M + H]⁺B166: 1-cyclohexyl-N- (2-fluorobenzyl)butan- 2-amine hydrochloride

¹H NMR (DMSO): δ 8.86-8.84 (m, 2H), 7.72-7.65 (m, 1H), 7.49-7.48 (m,1H), 7.34-7.28 (m, 2H), 4.25-4.10 (m, 2H), 3.15-3.05 (m, 1H), 1.73-0.84(m, 18H); Mass: m/z = 264 [M − HCl + H]⁺ B213: N-benzyl-1-(2,3-dihydro-1H-inden-1- yl)methanamine hydrochloride

¹H NMR (DMSO): δ 9.70-9.10 (m, 2H), 7.65-7.55 (m, 2H), 7.45-7.35 (m,3H), 7.25-7.10 (m, 4H), 4.30-4.10 (m, 2H), 3.60-3.55 (m, 1H), 3.33-3.30(m, 1H), 3.00-2.75 (m, 3H), 2.35-2.20 (m, 1H), 2.05-1.85 (m, 1H); Mass:m/z = 238 [M − HCl + H]⁺ B214: N-benzyl-1- (1,2,3,4-tetrahydronaphthalen-1- yl)methanamine hydrochloride

¹H NMR (DMSO): δ 9.55-9.40 (m, 1H), 9.20-9.05 (m, 1H), 7.75-7.05 (m,9H), 4.30-4.10 (m, 2H), 3.35-3.25 (m, 1H), 3.20-3.00 (m, 2H), 2.75-2.65(m, 2H), 2.05-0.60 (m, 4H); Mass: m/z = 252 [M − HCl + H]⁺ B215:N-benzyl-2- (piperidin-4- yl)ethanamine hydrochloride

¹H NMR (DMSO): δ 9.45-9.20 (m, 2H), 8.95-8.55 (m, 2H), 7.64-7.38 (m,5H), 4.15-4.05 (m, 2H), 3.30-3.20 (m, 2H), 3.00-2.75 (m, 4H), 1.85-1.20(m, 7H). B216: tert-butyl 4-(2- (benzylamino)ethyl)piperidine-1-carboxylate

¹H NMR (DMSO): δ 7.60-7.40 (m, 5H), 4.18-4.10 (m, 2H), 3.95-3.80 (m,2H), 2.95-2.85 (m, 2H), 2.75-2.60 (m, 2H), 1.70-0.90 (m, 16H). B218:4-(2- (benzylamino)ethyl) cyclohexanone

¹H NMR (DMSO): δ 7.50-7.10 (m, 5H), 4.15-4.10 (m, 2H), 3.75-3.65 (m,2H), 2.20-1.10 (m, 11H); Mass: m/z = 232 [M + H]⁺ B219: (E)-N-benzyl-4-cyclohexylbut-3-en-2- amine

¹H NMR (DMSO): δ 7.50-7.20 (m, 5H), 3.90-3.60 (m, 2H), 3.40-3.20 (m,1H), 2.90-2.80 (m, 1H), 1.80-0.80 (m, 15H); Mass: m/z = 244 [M + H]⁺

Synthetic Scheme 2

For example, N-benzyl-2-cyclohexyl-1-cyclopropylethanamine (B167) wassynthesized as follows: N-benzyl-2-cyclohexyl-1-cyclopropylethanamine

Synthetic Scheme 2

Step 1: See Scheme 1, step 1

Step 2: Preparation of 5

To a solution of 4 (565 mg, 8.005 mmol, 1 eq) in THF (14 mL, c=0.25) wasadded dropwise DPPA (1.11 g, 4.032 mmol, 1.2 eq) and DBU (614 mg, 4.032mmol, 1.2 eq) at 0° C. and the reaction mixture was stirred at 50° C.overnight. After completion, the reaction mixture was washed with water(20 mL) and extracted with EA (2×20 mL). The combined organic phaseswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuum. The residue was purified by column chromatography to give thedesired product 5 (348.8 mg, yield=50%) as an oil.

Step 3: Preparation of 6

To a solution of 5 (267 mg, 1.382 mmol, 1 eq) in THF (7 mL, c=0.2) wasadded Pd/C (20% wt, 53 mg). H₂ was bubbled through the reaction mixtureto saturate the solution. The reaction mixture was stirred at roomtemperature for 0.5 h. After completion, the reaction solution wasfiltered and washed with EtOH (4×30 mL). The filtrate was concentratedin vacuum and the residue was purified on a silica gel column to givethe product 6 (125 mg, yield=54%) as a yellow solid.

Step 4: Preparation of B167

To a solution of 6 (63 mg, 0.377 mmol, 1 eq) in MeOH (3.4 mL, c=0.2) wasadded benzaldehyde (147 mg, 1.382 mmol, 4 eq) and MgSO₄ (62 mg). Thereaction mixture was stirred at 40° C. for 1 h. After that, AcOH (0.1mL) and NaBH₃CN (91 mg, 1.4415 mmol, 3 eq) was added and the resultingmixture was stirred at 80° C. overnight. After completion, thesuspension was concentrated in vacuum and the residue was purified bycolumn chromatography to give the desired product (8.5 mg, yield=9%) asa yellow oil. After that, the product was dissolved in a solution ofHCl/MeOH (4M, 0.5 mL) again and the resulting mixture was concentratedin vacuum to give the desired product B167 (9.5 mg, yield=95%) as ayellow oil. ¹H NMR (400 MHz, DMSO): δ 9.00-8.70 (m, 2H), 7.60-7.35 (m,5H), 4.23-4.10 (m, 2H), 3.30-3.25 (m, 1H), 1.90-0.65 (m, 14H), 0.55-0.50(m, 2H), 0.28-0.25 (m, 2H). Mass: m/z=258 [M+H]⁺

The following compounds were synthesized via a similar route:

Compound Name, ID Structure Data of ¹H NMR (400 MHz), MS B169;N-benzyl-2- cyclohexyl-1- phenylethanamine hydrochloride

¹H NMR (DMSO): δ 9.52 (brs, 1H), 9.33 (brs, 1H), 7.54-7.31 (m, 10H),4.31 (brs, 1H), 4.06 (brs, 1H), 3.70 (brs, 1H), 1.99-0.86 (m, 13H);Mass: m/z = 294 [M − HCl + H]⁺ B168; 2- (benzylamino)-3-cyclohexylpropan-1-ol

¹H NMR (DMSO): δ 8.88-8.60 (m, 2H), 7.53-7.44 (m, 2H), 7.42-7.31 (m,3H), 4.28-4.10 (m, 2H), 3.72-3.71 (m, 1H), 3.57-3.56 (m, 1H), 3.11-3.01(m, 1H), 1.78-0.72 (m, 13H); Mass: m/z = 248 [M + H]⁺ B202; N-benzyl-1-cyclohexyl-3- methoxypropan-2- amine hydrochloride

¹H NMR (DMSO): δ 8.90-8.71 (m, 2H), 7.60-7.38 (m, 5H), 4.28-4.10 (m,2H), 3.72-3.71 (m, 2H), 3.58-3.56 (m, 1H), 3.35 (s, 3H), 1.78-0.72 (m,13H); Mass: m/z = 262 [M − HCl + H]⁺ B203; methyl 2- (benzylamino)-3-cyclohexylpropanoate hydrochloride

¹H NMR (DMSO): δ 9.91 (brs, 1H), 9.64 (brs, 1H), 7.53-7.35 (m, 5H),4.19-4.10 (m, 2H), 4.00 (brs, 1H), 3.75 (s, 3H), 1.84-0.83 (m, 13H);Mass: m/z = 276 [M − HCl + H]⁺ B204; 2- (benzylamino)-3-cyclohexylpropanoic acid

¹H NMR (DMSO): δ 13.92 (brs, 1H), 9.59 (brs, 1H), 7.53-7.43 (m, 5H),4.20-4.10 (m, 2H), 3.81 (s, 1H), 3.46-3.41 (m, 1H), 1.76-0.84 (m, 13H);Mass: m/z = 262 [M + H]⁺ B205; 2- (benzylamino)-3- cyclohexylpropanamidehydrochloride

¹H NMR (DMSO): δ 9.30 (brs, 2H), 8.09 (s, 1H), 7.73 (s, 1H), 7.51-7.42(m, 5H), 4.04 (s, 2H), 3.67 (s, 1H), 1.81-0.80 (m, 13H); Mass: m/z = 261[M − HCl + H]⁺ B210; tert-butyl benzyl(1- cyclohexyl-3- oxopropan-2-yl)carbamate

¹H NMR (DMSO): δ 9.40 (s, 1H), 7.40-7.15 (m, 5H), 4.15-4.10 (m, 2H),3.95-3.80 (m, 1H), 1.70- 0.65 (m, 22H); Mass: m/z = 246 [M − Boc + H]⁺

Synthetic Scheme 3

N-benzyl-2,3-dihydro-1H-inden-2-amine hydrochloride (B206) wassynthesized according to Synthetic Scheme 3.

Synthetic Scheme 3

To a solution of 7 (1 g, 5.915 mmol, 1 eq) in CH₃CN (12 mL, c=0.5) wasadded BnBr (1.51 g, 8.87 mmol, 1.5 eq), K₂CO₃ (3.27 g, 23.66 mmol, 4 eq)and KI (295 mg, 1.775 mmol, 0.3 eq) and the reaction mixture wasrefluxed at room temperature for 4 h. After completion, the reactionmixture was washed with water (20 mL) and extracted with EA (2×20 mL).The combined organic phases were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by columnchromatography to give the desired product (421 mg, yield=32%) as a oil.After that, the product was dissolved in a solution of HCl/MeOH (4M, 2.0mL) again and the resulting mixture was concentrated in vacuum to givethe desired product B206 (480 mg, yield=95%) as a yellow oil. ¹H NMR(400 MHz, DMSO): δ 9.80-9.55 (m, 1H), 7.70-7.60 (m, 2H), 7.50-7.35 (m,3H), 7.25-7.10 (m, 4H), 4.25-4.15 (m, 2H), 4.05-3.90 (m, 1H), 3.35-3.25(m, 2H), 3.25-3.15 (m, 2H). Mass: m/z=224 [M−HCl+H]⁺

The following compounds were synthesized via a similar route:

Compound Name, ID Structure Data of ¹H NMR (400 MHz), MS B207;(R)-N-benzyl- 2-cyclohexyl-1- phenylethanamine hydrochloride

¹H NMR (DMSO): δ 9.60-9.35 (m, 2H), 7.70- 7.10 (m, 8H), 4.90-4.78 (m,1H), 4.25-4.15 (m, 2H), 3.20-3.05 (m, 1H), 2.95-2.80 (m, 1H), 2.51-2.50(m, 1H), 2.35-2.25 (m, 1H); Mass: m/z = 242 [M + H]⁺. B208;(S)-N-benzyl- 6-fluoro-2,3- dihydro-1H-inden-1- amine hydrochloride

¹H NMR (DMSO): δ 9.60-9.35 (m, 2H), 7.70- 7.10 (m, 8H), 4.90-4.78 (m,1H), 4.25-4.15 (m, 2H), 3.20-3.05 (m, 1H), 2.95-2.80 (m, 1H), 2.51-2.50(m, 1H), 2.35-2.25 (m, 1H); Mass: m/z = 242 [M + H]⁺ B209; (S)-N-benzyl-6-methoxy-2,3- dihydro-1H-inden-1- amine hydrochloride

¹H NMR (DMSO): δ 9.60-9.56 (m, 2H), 7.65- 7.60 (m, 2H), 7.45-7.35 (m,4H), 7.30-7.20 (m, 1H), 7.00-6.90 (m, 1H), 4.75 (s, 1H), 4.19 (s, 2H),3.76 (s, 3H), 3.10-3.00 (m, 1H), 2.85-2.75 (m, 1H), 2.55-2.45 (m, 1H),2.35-2.23 (m, 1H); Mass: m/z = 254 [M − HCl + H]⁺ B211; (1S,2R)-N-benzyl-2-(3,4- difluorophenyl) cyclopropanamine hydrochloride

¹H NMR (DMSO): δ 9.88 (brs, 2H), 7.54 (s, 2H), 7.41-7.31 (m, 4H),7.24-7.19 (m, 1H), 7.04-6.99 (m, 1H), 4.27 (s, 2H), 2.88 (s, 1H), 2.50(s, 1H), 1.57-1.56 (m, 1H), 1.35-1.30 (m, 1H); Mass: m/z = 260 [M −HCl + H]⁺ B212; N-benzyl-2- (4,4- difluorocyclohexyl) ethanaminehydrochloride

¹H NMR (DMSO): δ 9.25-8.90 (m, 2H), 7.55- 7.30 (m, 5H), 4.15-4.05 (m,2H), 2.95-2.85 (m, 2H), 2.00-1.05 (m, 11H); Mass: m/z = 254 [M + H]⁺B220; 3- ((benzylamino) methyl)-7- methoxybenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride

¹H NMR (DMSO): δ 8.18-8.05 (m, 2H), 7.75- 7.65 (m, 1H), 7.40-7.25 (m,5H), 7.05-6.85 (m, 2H), 4.70-4.65 (m, 1H), 4.40-4.30 (m, 2H), 4.15-4.05(m, 1H), 3.77 (s, 3H), 3.15-3.00 (m, 2H); Mass: m/z = 284 [M + H]⁺

Compound B255 was made according to Synthetic Scheme 4:

Synthetic Scheme 4

Reference: WO 2007/017267, 15 Feb. 2007.

Compound Name Structure Data of ¹H NMR (400 MHz), MS B255; (2-((2-cyclohexylethylamino) methyl)phenyl) methanol hydrochloride

¹H NMR (DMSO): δ 8.95-8.75 (m, 2H), 7.58- 7.25 (m, 4H), 5.85-5.71 (s,1H), 4.70-4.60 (m, 2H), 4.25-4.15 (m, 2H), 3.05-2.90 (m, 2H), 1.85-0.75(m, 13H); Mass: m/z = 248 [M + H]⁺

Synthetic Scheme 5

The synthetic scheme was similar to that of synthetic scheme 3 and thecorresponding data were summarized as follows:

Compound Name, ID Structure Data of ¹H NMR (400 MHz); MS B340; 2-((2-cyclohexylethylamino) methyl)phenylboronic acid

¹H NMR (DMSO): δ 7.62-7.45 (m, 1H), 7.25- 7.00 (m, 3H), 4.05-3.85 (m,2H), 2.80-2.65 (m, 2H), 1.90 (s, 2H), 1.70-0.68 (m, 13H); Mass: m/z =262 [M + H]⁺ B376; 2-((2- cyclohexylethylamino) methyl)benzylboronicacid

¹H NMR (DMSO): δ 7.25-6.90 (m, 4H), 3.90- 3.80 (m, 2H), 3.78-3.32 (m,2H), 3.05-2.85 (m, 2H), 1.95-0.75 (m, 13H); Mass: m/z = 276 [M + H]⁺B225; 2-cyclohexyl-N- (2-(trifluoromethyl) benzyl) ethanaminehydrochloride

¹H NMR (DMSO): δ 9.68 (brs, 2H), 8.10-7.90 (m, 1H), 7.85-7.70 (m, 2H),7.65-7.55 (m, 1H), 4.30-4.20 (m, 2H), 2.97-2.82 (m, 2H), 1.66- 0.85 (m,13H); Mass: m/z = 286 [M − HCl + H]⁺ B228; 2-cyclohexyl-N-(2-ethylbenzyl) ethanamine hydrochloride

¹H NMR (DMSO): δ 9.14 (brs, 2H), 7.61-7.53 (m, 1H), 7.40-7.10 (m, 3H),4.16-4.08 (m, 2H), 3.10-2.90 (m, 2H), 2.80-2.65 (m, 2H), 1.80- 0.70 (m,18H); Mass: m/z = 246 [M − HCl + H]⁺ B254; N-(2- (aminomethyl)benzyl)-2- cyclohexylethanamine hydrochloride

¹H NMR (DMSO): δ 9.17 (brs, 2H), 8.44 (brs, 2H), 7.70-7.42 (m, 4H),4.35-4.15 (m, 4H), 3.10-2.98 (m, 2H), 1.80-0.80 (m, 13H); Mass: m/z =247 [M − 2HCl + H]⁺

Synthetic Scheme 6

Reference: WO 2007/017267, 15 Feb. 2007.

Compound Name, ID Structure Data of ¹H NMR (400 MHz); MS B339; 2-((2-cyclohexylethylamino) methyl)phenylboronic acid

¹H NMR (DMSO): δ 7.58-7.35 (m, 3H), 5.08-5.00 (m, 2H), 4.22-4.10 (m,2H), 2.85-2.78 (m, 2H), 1.70-0.70 (m, 13H); Mass: m/z = 274 [M + H]+B341; 2-cyclohexyl- N-(2-(trimethylsilyl)- benzyl)ethanaminehydrochloride

¹H NMR (DMSO): δ 9.50-8.80 (m, 2H), 7.80-7.30 (m, 4H), 4.25-4.10 (m,2H), 3.10-2.90 (m, 2H), 1.70-0.75 (m, 13H), 0.34 (s, 9H); Mass: m/z =290 [M + H]⁺ B226; 2-((2- cyclohexylethylamino) methyl)phenol

¹H NMR (DMSO): δ 7.10-6.95 (m, 2H), 6.80-6.55 (m, 2H), 3.85-3.75 (m,2H), 2.53-2.45 (m, 2H), 1.80-0.75 (m, 13H); Mass: m/z = 234 [M + H]⁺B227; 2-cyclohexyl- N-(2- isopropylbenzyl) ethanamine hydrochloride

¹H NMR (DMSO): δ 9.12 (brs, 2H), 7.60- 7.15 (m, 4H), 4.15-4.05 (m, 2H),3.05- 2.95 (m, 3H), 1.75-0.80 (m, 19H); Mass: m/z = 260 [M + H]⁺ B229;N-(biphenyl-2- ylmethyl)-2- cyclohexylethanamine hydrochloride

¹H NMR (DMSO): δ 9.34 (brs, 2H), 7.89- 7.86 (m, 1H), 7.51-7.31 (m, 8H),4.10- 3.95 (m, 2H), 2.80-2.65 (m, 2H), 1.83- 0.65 (m, 13H); Mass: m/z =294 [M + H]⁺ B230; 2-cyclohexyl- N-(2-(thiophen-2- yl)benzyl)ethanaminehydrochloride

¹H NMR (DMSO): δ 9.31 (brs, 2H), 7.86- 7.84 (m, 1H), 7.71-7.69 (m, 1H),7.50- 7.46 (m, 3H), 7.25-7.19 (m, 2H), 4.25- 4.15 (m, 2H), 2.90-2.78 (m,2H), 1.70- 0.70 (m, 13H); Mass: m/z = 300 [M − HCl + H]⁺ B231;2-cyclohexyl- N-(2-(pyridin-3- yl)benzyl)ethanamine hydrochloride

¹H NMR (DMSO): δ 9.53 (brs, 2H), 9.04 (s, 1H), 8.96 (s, 1H), 8.58 (s,1H), 8.09 (s, 1H), 8.08-7.99 (m, 1H), 7.63-7.55 (m, 2H), 7.45-7.43 (m,1H), 4.20-3.90 (m, 2H), 2.85-2.75(m, 2H), 1.75-0.65 (m, 13H); Mass: m/z= 295 [M − HCl + H]⁺ B232; 2-cyclohexyl- N-(2- phenoxybenzyl) ethanaminehydrochloride

¹H NMR (DMSO): δ 9.25-9.10 (m, 2H), 7.73-7.71 (m, 1H), 7.47-7.38 (m,3H), 7.23-7.19 (m, 2H), 7.10-7.08 (m, 2H), 6.86-6.84 (m, 1H), 4.25-4.10(m, 2H), 3.05-2.95 (m, 2H), 1.70-0.70 (m, 13H); Mass: m/z = 310 [M −HCl + H]⁺ B233; 2-cyclohexyl- N-(2- cyclopropylbenzyl) ethanaminehydrochloride

¹H NMR (DMSO): δ 9.30-9.17 (m, 2H), 7.65-7.40 (m, 1H), 7.35-7.20 (m,2H), 7.11-7.08 (m, 1H), 4.40-4.25 (m, 2H), 3.05-2.95 (m, 2H), 2.25-2.10(m, 1H), 1.85-0.60 (m, 17H); Mass: m/z = 258 [M − HCl + H]⁺ B234;2-cyclohexyl- N-(2-(naphthalen-2- yl)benzyl)ethanamine hydrochloride

¹H NMR (DMSO): δ 9.09 (brs, 2H), 8.05- 7.35 (m, 11H), 4.16-4.08 (m, 2H),2.75- 2.65 (m, 2H), 1.65-0.55 (m, 13H); Mass: m/z = 344 [M − HCl + H]⁺B235; 2-((2- cyclohexylethylamino) methyl)aniline hydrochloride

¹H NMR (DMSO): δ 10.30-8.30 (m, 2H), 7.68-7.20 (m, 4H), 4.43-4.11 (m,2H), 3.05-2.85 (m, 2H), 1.85-0.80 (m, 13H); Mass: m/z = 233 [M − HCl +H]⁺ B236; 2-cyclohexyl- N-(2-(furan-2- yl)benzyl)ethanaminehydrochloride

¹H NMR (DMSO): δ 9.31 (brs, 2H), 7.90- 7.70 (m, 3H), 7.55-7.35 (m, 2H),6.95- 6.60 (m, 2H), 4.29-4.38 (m, 2H), 3.00- 2.85 (m, 2H), 1.80-0.75 (m,13H); Mass: m/z = 284 [M − HCl + H]⁺ B237; 2-((2- cyclohexylethylamino)methyl)-N,N- dimethylaniline hydrochloride

¹H NMR (DMSO): δ 9.08 (brs, 2H), 7.75- 7.20 (m, 4H), 4.36-4.24 (m, 2H),3.05- 2.95 (m, 2H), 2.85 (s, 6H), 1.75-0.80 (m, 13H); Mass: m/z = 261 [M− HCl + H]⁺ B238; 2-cyclohexyl- N-(2-(naphthalen-1- yl)benzyl)ethanaminehydrochloride

¹H NMR (DMSO): δ 8.06 (brs, 1H), 8.04 (brs, 1H), 8.15-8.05 (m, 2H),7.90-7.82 (m, 1H), 7.70-7.20 (m, 8H), 3.95-3.85 (m, 1H), 3.75-3.60 (m,1H), 2.60-2.50 (m, 2H), 1.65-0.50 (m, 13H); Mass: m/z = 344 [M − HCl +H]⁺ B253; 2-cyclohexyl- N-(2- methoxybenzyl) ethanamine hydrochloride

¹H NMR (400 MHz, DMSO): δ 9.20-8.50 (m, 2H), 7.52-7.38 (m, 2H),7.18-6.95 (m, 2H), 4.15-4.05 (m, 2H), 3.80 (s, 3H), 3.00- 2.75 (m, 2H),1.75-0.70 (m, 13H); Mass: m/z = 248 [M − HCl + H]⁺ B256; 2-((2-cyclohexylethylamino) methyl)phenyl acetate

¹H NMR (DMSO): δ 7.82-7.70 (m, 1H), 7.15-7.00 (m, 2H), 6.80-6.65 (m,2H), 3.85-3.78 (m, 2H), 3.05-2.95 (m, 2H), 2.55-2.45 (s, 3H), 1.80-0.70(m, 13H); Mass: m/z = 276 [M + H]⁺ B257; 2-((2- cyclohexylethylamino)methyl)benzoic acid hydrochloride

¹H NMR (DMSO): δ 13.50 (brs, 1H), 8.95-8.80 (m, 2H), 8.10-8.00 (m, 1H),7.75-7.55 (m, 3H), 4.50-4.32 (m, 2H), 3.10-2.90 (m, 2H), 1.80-0.70 (m,13H); Mass: m/z = 262 [M − HCl + H]⁺ B258; methyl 2-((2-cyclohexylethylamino) methyl)benzoate hydrochloride

¹H NMR (DMSO): δ 8.88 (brs, 2H), 8.10- 8.00 (m, 1H), 7.72-7.50 (m, 3H),4.45- 4.30 (m, 2H), 3.85 (s, 3H), 3.05-2.90 (m, 2H), 1.78-0.75 (m, 13H);Mass: m/z = 276 [M − HCl + H]⁺ B259; 2-((2- cyclohexylethylamino)methyl)benzamide trifluoroacetate

¹H NMR (DMSO): δ 8.77 (brs, 2H), 8.35 (s, 1H), 7.91 (s, 1H), 7.75-7.53(m, 4H), 4.25-4.10 (m, 2H), 3.12-2.90 (m, 2H), 1.80-0.70 (m, 13H); Mass:m/z = 261 [M − TFA + H]⁺ B328; 2-cyclohexyl- N-(2-((tetrahydro-2H-pyran-2- yl)methoxy)benzyl) ethanamine hydrochloride

¹H NMR (400 MHz, DMSO): δ 9.15-8.90 (m, 2H), 7.49-7.32 (m, 2H),7.15-6.90 (m, 2H), 4.10-3.90 (m, 5H), 3.76-3.65 (m, 1H), 3.48-3.30 (m,1H), 2.95-2.80 (m, 2H), 1.90-0.70 (m, 19H); Mass: m/z = 332 [M − HCl +H]⁺ B329; 2-cyclohexyl- N-(2- ((tetrahydrofuran-2- yl)methoxy)benzyl)ethanamine

¹H NMR (DMSO): δ 7.41-7.30 (m, 2H), 7.06-6.80 (m, 2H), 4.21-4.20 (m,1H), 4.06-3.86 (m, 2H), 3.95-3.85 (m, 2H), 3.85-3.60 (m, 2H), 2.80-2.72(m, 2H), 2.05-0.70 (m, 17H); Mass: m/z = 318 [M + H]⁺ B330;2-cyclohexyl- N-(2- ((tetrahydrofuran-3- yl)methoxy)benzyl) ethanamine

¹H NMR (DMSO): δ 7.43-7.35 (m, 2H), 7.08-6.99 (m, 2H), 4.01-3.94 (m,4H), 3.85-3.80 (m, 2H), 3.68-3.60 (m, 2H), 2.88-2.85 (m, 2H), 2.85-2.62(m, 1H), 2.10-1.90 (m, 1H), 1.80-0.70 (m, 14H); Mass: m/z = 318 [M + H]⁺B331; 2-cyclohexyl- N-(2-((tetrahydro-2H- pyran-4- yl)methoxy)benzyl)ethanamine

¹H NMR (DMSO): δ 7.35-7.25 (m, 2H), 6.92-6.88 (m, 2H), 3.91-3.82 (m,6H), 3.45-3.31 (m, 2H), 2.68-2.64 (m, 2H), 2.05-1.90 (m, 1H), 1.70-0.84(m, 17H); Mass: m/z = 332 [M + H]⁺ B378; 3-(2-((1- cyclohexylpropan-2-ylamino)methyl) phenyl)propan-1-ol

¹H NMR (DMSO): δ 7.56-7.35 (m, 1H), 7.30-7.08 (m, 3H), 3.95-3.78 (m,2H), 3.45-3.32 (m, 2H), 3.10-2.85 (m, 1H), 2.85-2.65 (m, 2H), 1.85-0.75(m, 18H); Mass: m/z = 290 [M + H]⁺ B399; 3-(2-((1- cyclohexylpropan-2-ylamino)methyl) phenyl)propanamide trifluoroacetate

¹H NMR (DMSO): δ 8.76 (brs, 2H), 7.63 (s, 1H), 7.43-7.00 (m, 5H),4.30-4.08 (m, 2H), 3.29-3.22 (m, 1H), 2.85-2.78 (m, 2H), 2.60-2.52 (m,2H), 1.70-0.75 (m, 16H); Mass: m/z = 303 [M − TFA + H]⁺ B400; methyl3-(2- ((1-cyclohexylpropan- 2- ylamino)methyl) phenyl)propanoatehydrochloride

¹H NMR (DMSO): δ 8.73 (brs, 1H), 8.65 (brs, 1H), 7.60-7.05 (m, 4H),4.45-4.16 (m, 2H), 3.75-3.50 (m, 3H), 2.95-2.85 (m, 1H), 2.60-2.55 (m,2H), 1.85-0.65 (m, 18H); Mass: m/z = 318 [M + H]⁺ B401; 3-(2-((1-cyclohexylpropan-2- ylamino)methyl) phenyl)propanoic acidtrifluoroacetate

¹H NMR (DMSO): δ 8.60 (brs, 1H), 8.54 (brs, 1H), 7.47-7.45 (m, 1H),7.37-7.29 (m, 3H), 4.32-4.20 (m, 2H), 3.50-3.28 (m, 1H), 2.95-2.88 (m,2H), 2.60-2.55 (m, 2H), 1.85-0.75 (m, 16H); Mass: m/z = 304 [M + H]⁺

The compounds listed below were synthesized according to the followinggeneral procedure:

Amine 1 (0.5 mmol), aldehyde 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated anddissolved in 0.5 ml of DMSO. The residue was purified using HPLC.Yields: 31-67%.

Example 2: General Compound Syntheses 2

Synthesis of target compounds was carried out following the generalscheme below:

Amine 1 (0.5 mmol), aldehyde 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated andoptionally dissolved in 0.5 ml of DMSO. The residue was purified usingHPLC. Yield: 31-67%

1H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J=7.3 Hz, 1H), 7.29 (dtd, J=27.0,14.5, 12.6, 7.4 Hz, 7H), 7.17 (t, J=7.5 Hz, 1H), 6.26 (s, 1H), 3.75 (s,2H), 2.80 (t, J=7.3 Hz, 2H), 2.69 (t, J=7.7 Hz, 2H), 2.54 (s, 1H);

1H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.74 (s, 1H), 7.63 (d,J=7.0 Hz, 2H), 7.45 (dd, J=8.1, 6.2 Hz, 2H), 7.44-7.36 (m, 1H), 5.37 (d,J=3.7 Hz, 1H), 4.40 (d, J=7.1 Hz, 1H), 2.82 (p, J=11.9, 10.4 Hz, 2H),2.58 (t, J=8.0 Hz, 2H), 1.98 (d, J=6.8 Hz, 3H), 1.94-1.88 (m, 2H), 1.74(q, J=4.9 Hz, 2H), 1.50 (ddtd, J=16.3, 10.4, 5.5, 3.0 Hz, 4H);

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.21 (m, 4H), 7.20 (s, 1H), 7.16 (ddd,J=8.6, 5.5, 2.5 Hz, 1H), 5.32 (s, 1H), 3.70 (s, 2H), 2.63 (t, J=7.0 Hz,2H), 2.32-2.20 (m, 3H), 2.19 (d, J=8.8 Hz, 3H), 1.83 (p, J=7.5 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J=6.6 Hz, 4H), 7.17 (d, J=6.4 Hz,1H), 5.08 (t, J=7.2 Hz, 1H), 3.70 (s, 2H), 2.52 (d, J=7.3 Hz, 2H), 2.12(q, J=7.2 Hz, 2H), 1.68 (s, 3H), 1.61 (s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.20 (m, 4H), 7.16 (t, J=7.0 Hz, 1H),5.52 (s, 1H), 3.64 (s, 2H), 2.01-1.94 (m, 4H), 1.67-1.51 (m, 5H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J=6.5 Hz, 5H), 7.16 (dd, J=8.1, 4.9Hz, 1H), 6.08 (dd, J=5.7, 3.0 Hz, 1H), 5.88 (dd, J=5.8, 2.8 Hz, 1H),3.68 (s, 2H), 2.73 (s, 2H), 2.50 (d, J=14.5 Hz, 1H), 2.06 (qt, J=8.0,3.7 Hz, 1H), 1.83 (ddd, J=12.2, 8.9, 3.8 Hz, 1H), 1.40-1.32 (m, 1H),1.26 (dd, J=13.5, 6.7 Hz, 1H), 1.21 (dd, J=7.9, 4.3 Hz, 2H), 0.49 (dt,J=11.6, 3.3 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.35-7.21 (m, 4H), 7.17 (tq, J=5.7, 3.7, 3.0Hz, 1H), 5.53 (t, J=6.4 Hz, 1H), 3.69 (s, 2H), 2.56 (t, J=7.0 Hz, 2H),2.50 (s, 1H), 2.12 (d, J=7.0 Hz, 1H), 2.06 (dq, J=10.8, 6.1, 5.0 Hz,5H), 1.88 (s, 6H), 1.72 (p, J=6.0 Hz, 2H), 1.44 (dt, J=10.4, 5.5 Hz,4H).

1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J=4.4 Hz, 4H), 7.16 (p, J=4.3 Hz,1H), 5.46-5.40 (m, 1H), 3.69 (s, 2H), 2.36 (s, 2H), 2.03 (tt, J=6.2, 3.1Hz, 2H), 1.87 (s, 1H), 1.88-1.78 (m, 1H), 1.62-1.47 (m, 5H), 1.00 (s,6H), 0.95 (d, J=2.1 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 6.99-6.87 (m, 3H), 5.38 (s, 1H), 3.00 (s,2H), 2.68 (t, J=6.9 Hz, 2H), 2.34 (s, 6H), 2.09 (t, J=7.0 Hz, 2H), 1.96(d, J=6.2 Hz, 2H), 1.90 (d, J=14.3 Hz, 0H), 1.90 (s, 2H), 1.65-1.48 (m,4H), 0.93 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (dd, J=12.9, 5.5 Hz, 4H), 7.15 (t,J=7.0 Hz, 1H), 3.00 (s, 2H), 2.71 (s, 1H), 2.49-2.41 (m, 1H), 2.27 (t,J=10.8 Hz, 1H), 2.21-2.08 (m, 2H), 1.84-1.76 (m, 1H), 1.60 (d, J=21.6Hz, 8H).

1H NMR (400 MHz, Chloroform-d) δ 7.22-7.03 (m, 2H), 7.03-6.96 (m, 1H),5.45 (tt, J=3.7, 1.7 Hz, 1H), 3.73 (s, 2H), 2.65 (t, J=6.9 Hz, 2H), 2.14(t, J=7.0 Hz, 2H), 1.98 (tdd, J=6.2, 3.8, 1.8 Hz, 2H), 1.92-1.84 (m,2H), 1.66-1.49 (m, 3H), 1.35-1.29 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.21 (m, 4H), 7.16 (td, J=6.5, 6.1, 2.5Hz, 1H), 3.68 (s, 2H), 2.56-2.44 (m, 3H), 2.16 (d, J=4.7 Hz, 1H), 1.93(d, J=3.5 Hz, 1H), 1.42 (dqt, J=21.5, 8.2, 3.5 Hz, 5H), 1.30 (d, J=9.8Hz, 1H), 1.23 (s, 1H), 1.22-0.96 (m, 4H).

1H NMR (500 MHz, Chloroform-d) δ 7.29 (q, J=7.3, 6.8 Hz, 1H), 7.21 (d,J=7.2 Hz, 2H), 5.38 (d, J=3.9 Hz, 1H), 2.89 (t, J=6.7 Hz, 1H), 2.81 (t,J=7.0 Hz, 1H), 2.68 (t, J=7.0 Hz, 1H), 2.11 (t, J=7.0 Hz, 1H), 1.96-1.90(m, 1H), 1.56 (ddt, J=8.6, 6.4, 4.0 Hz, 1H), 1.50 (dtt, J=9.3, 6.1, 2.8Hz, 1H), 1.31 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=5.0 Hz, 1H), 6.92-6.83 (m, 2H),5.38 (s, 1H), 3.89 (s, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.50 (s, 0H), 2.07(t, J=7.3 Hz, 2H), 1.97 (s, 3H), 1.88 (d, J=6.9 Hz, 2H), 1.57 (dq,J=19.1, 5.2 Hz, 5H).

1H NMR (400 MHz, Chloroform-d) δ 8.56-8.46 (m, 2H), 7.69-7.62 (m, 1H),7.24 (dd, J=7.6, 4.8 Hz, 1H), 5.45 (s, 1H), 3.80 (s, 2H), 2.67 (t, J=6.9Hz, 2H), 2.14 (t, J=6.9 Hz, 2H), 1.98 (s, 2H), 1.86 (d, J=7.4 Hz, 2H),1.56 (dq, J=11.7, 6.3 Hz, 3H), 1.22 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 3H), 7.23 (d, J=7.6 Hz, 1H), 7.16(s, 1H), 3.84 (d, J=11.6 Hz, 1H), 3.68 (s, 1H), 3.29 (d, J=10.6 Hz, 2H),3.20 (d, J=4.5 Hz, 1H), 2.56 (d, J=12.9 Hz, 2H), 1.79 (s, 1H), 1.58-1.49(m, 2H), 1.46 (s, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J=4.5 Hz, 3H), 7.28-7.20 (m,1H), 3.80 (s, 2H), 2.70 (t, J=6.3 Hz, 2H), 2.44 (t, J=6.3 Hz, 2H), 2.33(t, J=5.2 Hz, 4H), 1.90 (s, 1H), 1.55 (t, J=5.7 Hz, 3H), 1.41 (p, J=5.8Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.36-7.28 (m, 3H), 7.28-7.21 (m, 1H),3.77 (d, J=1.9 Hz, 2H), 3.00 (t, J=10.0 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H),2.52 (t, J=12.1 Hz, 1H), 2.24 (t, J=11.3 Hz, 1H), 2.05 (s, 5H), 1.79 (d,J=13.2 Hz, 1H), 1.63 (d, J=13.4 Hz, 1H), 1.41 (dtd, J=21.0, 15.1, 13.7,5.1 Hz, 4H), 1.04 (tt, J=13.0, 6.5 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.25 (m, 2H), 3.66 (s, 1H), 2.59-2.43(m, 3H), 1.90 (dd, J=13.0, 3.4 Hz, 1H), 1.33 (p, J=6.9 Hz, 1H),1.27-1.13 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.31(d, J=7.6 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 3.62 (s, 2H), 2.44 (d, J=13.6Hz, 1H), 2.44 (s, 2H), 2.05 (s, 1H), 1.63 (d, J=11.4 Hz, 5H), 1.29 (d,J=7.4 Hz, 3H), 1.15 (h, J=12.3 Hz, 3H), 0.83 (d, J=11.1 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.35-7.27 (m, 1H), 7.23 (t, J=9.0 Hz,1H), 4.45 (s, 1H), 3.79 (s, 1H), 3.39 (s, 1H), 2.64 (t, J=7.5 Hz, 1H),1.68 (d, J=12.4 Hz, 2H), 1.40 (q, J=7.2 Hz, 1H), 1.29 (s, 1H), 1.17 (p,J=12.4 Hz, 1H), 0.90 (q, J=11.2 Hz, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.33 (s, 1H), 7.27-7.16 (m, 3H), 3.76(s, 2H), 2.62 (t, J=7.4 Hz, 2H), 1.72-1.60 (m, 5H), 1.40 (q, J=7.1 Hz,2H), 1.34 (s, 2H), 1.33-1.22 (m, 1H), 1.25 (s, 1H), 1.19 (d, J=9.1 Hz,1H), 1.20-1.09 (m, 1H), 0.93 (d, J=11.6 Hz, 1H), 0.88 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.18(s, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.88 (td, J=7.4, 2.1 Hz, 1H), 6.36 (d,J=2.7 Hz, 1H), 4.00 (s, 2H), 2.61-2.52 (m, 2H), 2.53 (s, 1H), 2.02 (s,2H), 1.67 (d, J=12.4 Hz, 5H), 1.37 (q, J=6.9 Hz, 3H), 1.18 (h, J=11.9,11.2 Hz, 3H), 0.88 (t, J=11.2 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.18 (t, J=7.8 Hz, 1H), 6.99 (s, 1H), 6.90(d, J=7.5 Hz, 1H), 6.79-6.72 (m, 1H), 3.78 (d, J=3.0 Hz, 5H), 2.62 (t,J=7.5 Hz, 2H), 1.69 (d, J=12.6 Hz, 5H), 1.46-1.38 (m, 2H), 1.32 (s, 1H),1.18 (dt, J=22.3, 12.6 Hz, 3H), 0.93 (d, J=11.5 Hz, 1H), 0.88 (s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=7.6 Hz, 1H), 7.44 (d, J=5.4Hz, 1H), 7.40-7.24 (m, 4H), 4.09 (s, 2H), 2.68 (t, J=7.4 Hz, 2H), 1.69(s, 1H), 1.52 (s, 2H), 1.43 (q, J=7.3 Hz, 2H), 1.33 (s, 1H), 1.18 (h,J=12.1 Hz, 3H), 0.89 (q, J=11.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.24-7.15 (m, 2H), 7.12 (d, J=12.2 Hz, 2H),3.74 (s, 2H), 3.66 (s, 2H), 2.53 (d, J=6.7 Hz, 2H), 1.68 (d, J=13.2 Hz,5H), 1.33 (s, 3H), 1.24 (s, 1H), 1.19 (d, J=12.4 Hz, 2H), 0.88 (s, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.12 (t, J=7.7 Hz, 1H), 6.75 (dd,J=18.8, 10.6 Hz, 3H), 6.02 (s, 3H), 3.71 (s, 2H), 2.70 (t, J=7.9 Hz,2H), 1.61 (s, 1H), 1.47 (q, J=7.4 Hz, 2H), 1.31-1.06 (m, 4H), 0.94-0.80(m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 2H), 7.23 (d, J=7.9 Hz, 2H), 7.16(t, J=2.9 Hz, 2H), 6.97 (dd, J=9.7, 5.6 Hz, 2H), 6.90 (d, J=7.2 Hz, 2H),6.45 (s, 2H), 3.94 (d, J=3.6 Hz, 4H), 2.60 (t, J=7.0 Hz, 4H), 1.68 (d,J=13.5 Hz, 11H), 1.39-1.31 (m, 6H), 1.23 (s, 1H), 1.20 (s, 5H), 1.17 (s,1H), 1.10 (d, J=10.7 Hz, 1H), 0.88 (d, J=12.1 Hz, 5H).

1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 2H), 9.35 (s, 1H), 9.19 (d, J=10.5Hz, 1H), 7.64-7.57 (m, 2H), 7.42 (d, J=5.9 Hz, 3H), 4.11 (p, J=8.8, 7.0Hz, 2H), 3.18 (d, J=12.0 Hz, 2H), 3.05 (s, 2H), 2.84-2.74 (m, 1H), 2.16(dq, J=14.1, 6.5 Hz, 1H), 2.00 (dq, J=14.3, 7.2 Hz, 1H), 1.71 (td,J=30.9, 23.6, 10.6 Hz, 4H), 1.50-1.32 (m, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 7.10 (t, J=7.7 Hz, 1H),6.69 (d, J=11.1 Hz, 2H), 6.58 (d, J=8.0 Hz, 1H), 3.70 (s, 2H), 3.64 (s,2H), 2.64 (t, J=7.6 Hz, 2H), 1.40 (q, J=7.2 Hz, 2H), 1.29 (s, 1H), 1.24(d, J=13.0 Hz, 1H), 1.16 (dd, J=21.0, 11.6 Hz, 2H), 0.91 (t, J=11.6 Hz,2H).

1H NMR (400 MHz, DMSO-d6) δ 6.78 (d, J=7.6 Hz, 1H), 6.73 (td, J=7.6, 3.2Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 5.94 (d, J=3.3 Hz, 2H), 3.64 (d, J=3.3Hz, 2H), 2.51 (dd, J=8.4, 4.8 Hz, 3H), 1.67 (d, J=12.8 Hz, 5H), 1.32 (d,J=6.1 Hz, 3H), 1.23 (s, 1H), 1.21-1.09 (m, 2H), 0.89 (t, J=11.2 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.31 (d, J=10.3 Hz, 1H), 7.25 (d, J=9.0Hz, 1H), 4.69 (s, 1H), 3.78 (s, 1H), 2.65 (t, J=7.5 Hz, 1H), 1.41 (q,J=7.3 Hz, 1H), 1.32-1.21 (m, 1H), 1.16 (dd, J=21.4, 11.5 Hz, 1H), 0.90(q, J=11.6 Hz, 1H).

Example 3: General Compound Syntheses 3

Synthesis of target compounds was carried out following the schemebelow:

Amine 1 (0.5 mmol), benzaldehyde 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated anddissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield:31-59%.

1H NMR (400 MHz, DMSO-d6) δ 7.26 (p, J=6.9, 6.3 Hz, 4H), 7.18 (s, 1H),6.90-6.85 (m, 1H), 6.82-6.73 (m, 2H), 5.95 (s, 2H), 3.66 (s, 2H), 2.61(s, 2H), 1.83 (s, 1H), 0.74-0.63 (m, 3H).

1H NMR (400 MHz, DMSO-d6) δ 8.08-8.01 (m, 1H), 7.94-7.87 (m, 1H), 7.79(d, J=8.1 Hz, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.48 (dq, J=7.2, 3.6, 2.9 Hz,3H), 7.31 (dt, J=14.8, 7.5 Hz, 4H), 7.21 (t, J=7.1 Hz, 1H), 5.45 (s,2H), 5.43 (d, J=3.8 Hz, 0H), 3.79 (s, 2H), 2.86-2.78 (m, 1H), 2.69 (dd,J=12.2, 7.8 Hz, 1H), 2.31 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=4.5 Hz, 4H), 7.20 (p, J=4.1 Hz,1H), 6.90 (dd, J=9.6, 3.1 Hz, 1H), 6.77 (dd, J=8.7, 3.1 Hz, 1H), 5.22(s, 2H), 4.84 (s, 2H), 3.69 s, 2H), 2.67 (s, 4H), 2.13 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.22 (m, 4H), 7.17 (t, J=7.2 Hz, 1H),7.16-7.03 (m, 3H), 7.00 (d, J=6.4 Hz, 1H), 3.59 (d, J=7.1 Hz, 1H), 3.26(dd, J=14.1, 5.2 Hz, 1H), 2.99 (s, 1H), 2.90-2.77 (m, 3H), 1.73 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=4.5 Hz, 4H), 7.20 (dt, J=8.7, 4.3Hz, 1H), 7.03 (s, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H),4.46 (t, J=8.6 Hz, 2H), 3.69 (s, 2H), 3.11 (t, J=8.7 Hz, 2H), 2.68-2.59(m, 4H).

1H NMR (400 MHz, DMSO-d6) δ 7.32-7.21 (m, 4H), 7.17 (t, J=6.9 Hz, 1H),3.74 (d, J=13.5 Hz, 1H), 3.68 (d, J=13.5 Hz, 1H), 2.99 (s, 1H), 2.64 (d,J=6.2 Hz, 1H), 2.58 (dd, J=21.1, 9.9 Hz, 2H), 2.39-2.20 (m, 5H), 2.18(d, J=4.8 Hz, 1H), 2.18-2.09 (m, 1H), 1.99 (d, J=9.6 Hz, 1H), 1.90 (s,1H), 1.60 (d, J=10.2 Hz, 1H), 1.11 (d, J=10.2 Hz, 1H), 0.91 (dt, J=11.3,3.7 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 8.91 (dd, J=4.1, 1.9 Hz, 1H), 8.39-8.26 (m,2H), 8.20 (d, J=10.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.62 (d, J=6.8 Hz,1H), 7.52 (dq, J=8.1, 4.9, 3.5 Hz, 3H), 7.40 (s, 2H), 7.28 (q, J=7.8,7.4 Hz, 7H), 7.23-7.15 (m, 2H), 3.74 (s, 3H), 3.38 (t, J=7.4 Hz, 3H),2.87 (t, J=7.4 Hz, 3H), 2.54 (s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.35-7.21 (m, 4H), 7.20 (s, 1H), 7.11(t, J=7.4 Hz, 1H), 7.05 (td, J=7.3, 1.5 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H),3.83 (s, 2H), 2.71 (dd, J=12.2, 6.7 Hz, 1H), 2.67-2.54 (m, 2H), 2.46(td, J=15.6, 14.7, 6.2 Hz, 1H), 2.14 (ddt, J=13.3, 6.4, 2.1 Hz, 1H),1.75-1.61 (m, 2H), 1.45 (dq, J=9.2, 3.5, 2.5 Hz, 1H), 1.42-1.35 (m 1H.

1H NMR (400 MHz, DMSO-d6) δ 7.36-7.26 (m, 4H), 7.21 (t, J=6.9 Hz, 11H),6.87-6.76 (m, 2H), 6.81 (s, 2H), 4.33-4.25 (m, 1H), 4.25 (d, J=7.1 Hz,11H), 3.87 (dd, J=11.2, 7.4 Hz, 11H), 3.70 (s, 2H), 2.67 (t, J=7.0 Hz,2H), 2.54 (s, OH), 2.25 (s, 1H), 1.80-1.69 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=4.4 Hz, 4H), 7.20 (dt, J=8.7, 4.3Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.69 (d, J=2.1 Hz, 11H), 4.26 (ddd,J=20.7, 6.1, 3.1 Hz, 4H), 3.68 (s, 2H), 2.69-2.62 (m, 2H), 2.58 (s, 1H),2.62-2.52 (m, 2H), 2.01 (s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.47 (s, 1H), 7.35-7.25(m, 2H), 7.25 (s, 1H), 7.25-7.16 (m, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.50(s, 1H), 3.82 (s, 2H), 2.95 (s, 4H).

1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.97 (s, 1H), 7.63 (d, J=8.3Hz, 1H), 7.30 (t, J=6.9 Hz, 5H), 7.21 (s, 1H), 6.96 (d, J=8.3 Hz, 1H),3.72 (s, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.77 (s, 2H), 2.54 (s, 1H), 2.02(s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.29 (dt, J=20.2, 6.9 Hz, 4H), 3.78 (d,J=2.4 Hz, 2H), 2.96-2.86 (m, 2H), 2.16 (s, 1H), 2.08 (d, J=15.8 Hz, 2H),1.77-1.52 (m, 3H), 1.40-1.13 (m, 5H).

1H NMR (400 MHz, Chloroform-d) δ 7.36-7.28 (m, 8H), 7.25 (d, J=6.5 Hz,3H), 3.91 (dd, J=16.5, 12.8 Hz, 2H), 3.66 (d, J=12.8 Hz, 2H), 2.52 (tt,J=11.5, 6.2 Hz, 2H), 1.77 (s, 1H), 1.71 (s, 2H), 1.42-1.31 (m, 4H), 1.18(dd, J=12.8, 6.3 Hz, 1H), 1.09 (dd, J=10.6, 6.1 Hz, 7H).

1H NMR (400 MHz, Chloroform-d) δ 7.31 (p, J=6.9, 6.1 Hz, 2H), 7.25 (d,J=3.2 Hz, 1H), 4.25 (s, 1H), 3.79 (s, 1H), 2.64 (t, J=5.8 Hz, 1H),2.54-2.41 (m, 2H), 2.27 (dd, J=11.2, 2.1 Hz, 1H), 1.90-1.79 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.14 (m, 4H), 7.18-7.09 (m, 1H), 7.05(d, J=6.8 Hz, 2H), 4.96 (s, 4H), 3.72 (s, 2H), 2.76 (s, 4H), 1.58 (s,1H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J=6.7 Hz, 4H), 7.16 (t, J=6.8 Hz,1H), 4.43-4.32 (m, 1H), 4.26 (t, J=5.0 Hz, 1H), 3.69 (s, 2H), 2.04-1.94(m, 1H), 1.85 (tdd, J=11.4, 5.7, 2.8 Hz, 1H), 1.75 (ddd, J=12.7, 9.0,3.9 Hz, 1H), 1.65-1.53 (m, 2H), 1.48 (p, J=6.7, 6.0 Hz, 2H), 1.43 (s,1H), 1.35 (td, J=9.7, 4.2 Hz, 1H), 0.86 (dd, J=11.4, 5.1 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 4H), 7.16 (dq, J=7.0, 4.5, 3.2Hz, 1H), 3.76 (d, J=13.4 Hz, 1H), 3.64 (d, J=13.3 Hz, 1H), 2.65 (h,J=6.4 Hz, 1H), 1.64 (q, J=10.5, 8.6 Hz, 5H), 1.35 (ddd, J=16.2, 8.2, 4.9Hz, 1H), 1.32-1.14 (m, 2H), 1.17-1.04 (m, 1H), 1.00 (d, J=6.2 Hz, 3H),0.91-0.76 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.17 (m, 4H), 7.16 (dq, J=9.6, 4.4, 3.1Hz, 1H), 3.76 (d, J=13.3 Hz, 1H), 3.64 (d, J=13.3 Hz, 1H), 2.65 (h,J=6.3 Hz, 1H), 1.65 (t, J=6.6 Hz, 5H), 1.35 (ddd, J=15.6, 8.2, 4.9 Hz,1H), 1.32-1.22 (m, 1H), 1.15 (ddd, J=26.6, 14.4, 4.6 Hz, 2H), 1.10-0.97(m, 3H), 0.83 (dd, J=16.0, 6.9 Hz, 2H.

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.20 (m, 3H), 7.16 (td, J=6.2, 2.9 Hz,1H), 2.98 (s, 1H), 2.53-2.47 (m, 4H), 1.93 (s, 2H), 1.65 (q, J=12.4 Hz,5H), 1.49 (d, J=2.9 Hz, 4H), 1.24 (t, J=8.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 2H), 7.58 (d, J=6.9 Hz, 2H), 7.42(d, J=6.9 Hz, 3H), 6.75 (t, J=7.4 Hz, 2H), 6.67 (s, 1H), 6.39 (t, J=7.4Hz, 1H), 5.49 (s, 1H), 4.13 (s, 2H), 3.24 (t, J=5.5 Hz, 2H), 3.01-2.93(m, 2H), 2.85 (t, J=8.0 Hz, 2H), 2.66 (d, J=6.4 Hz, 2H), 1.77 (p, J=6.0,5.5 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=7.5 Hz, 2H), 7.24 (t, J=7.4 Hz,2H), 7.16 (t, J=7.0 Hz, 1H), 6.99 (td, J=7.7, 6.9, 2.6 Hz, 1H), 6.93 (d,J=6.0 Hz, 2H), 6.61 (d, J=7.8 Hz, 1H), 3.81-3.67 (m, 2H), 2.82 (t, J=6.1Hz, 2H), 2.69 (d, J=6.9 Hz, 2H), 2.54 (s, 1H), 1.86 (s, 2H), 1.91-1.73(m, 1H), 1.71-1.61 (m, 1H), 1.32 (dt, J=13.2, 6.5 Hz, 1H), 1.08 (dd,J=8.9, 4.6 Hz, 1H), 0.61-0.54 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.23 (m, 4H), 7.20 (s, 1H), 6.98 (d,J=7.3 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.69 (t, J=7.4 Hz, 1H), 3.69 (s,2H), 2.96 (s 2H) 263 (dt, J=11.9, 6.1 Hz, 4H), 2.54 (s, 1H), 2.01 (s,1H), 1.36 (s, 6H).

1H NMR (400 MHz, DMSO-d6) δ 7.37-7.24 (m, 7H), 7.23-7.09 (m, 5H), 7.06(d, J=6.1 Hz, 1H), 3.82 (d, J=15.7 Hz, 2H), 3.69 (d, J=13.4 Hz, 2H),3.16 (ddd, J=20.1, 14.0, 5.6 Hz, 2H), 2.84 (d, J=14.2 Hz, 2H), 2.75 (d,J=7.5 Hz, 1H), 2.66 (s, 1H), 2.54 (s, 1H), 1.99 (s, 1H), 1.90 (s, 1H),1.12 (d, J=6.3 Hz, 2H), 1.05 (d, J=6.3 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 8.19 (dd, J=8.4, 1.5 Hz, 1H), 7.96 (d, J=8.5Hz, 1H), 7.52-7.37 (m, 2H), 7.32-7.25 (m, 2H), 7.23 (dd, J=15.5, 7.6 Hz,3H), 7.21-7.12 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 3.97 (s, 3H), 3.75 (s,2H), 3.14 (t, J=7.4 Hz, 2H), 2.87 (q, J=8.0, 7.3 Hz, 2H), 1.68 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.31 (dt, J=11.4, 7.0 Hz, 4H), 7.25-7.17 (m,1H), 7.04 (d, J=8.4 Hz, 1H), 6.65 (dd, J=8.5, 2.7 Hz, 1H), 6.58 (d,J=2.6 Hz, 1H), 3.79-3.65 (m, 5H), 2.79 (dd, J=9.4, 4.8 Hz, 1H), 2.63(dd, J=7.8, 4.5 Hz, 3H), 2.55 (d, J=10.1 Hz, 1H), 2.07 (s, 1H), 1.88 (q,J=6.1, 5.5 Hz, 1H), 1.68 (s, 2H), 1.60 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (t, J=6.6 Hz, 2H), 7.25 (d, J=7.7 Hz,1H), 7.26-7.18 (m, 2H), 7.21-7.09 (m, 4H), 7.01 (ddd, J=12.0, 8.7, 5.9Hz, 6H), 3.69 (d, J=13.5 Hz, 1H), 3.53 (d, J=13.5 Hz, 1H), 3.27-3.16 (m,1H), 3.12 (td, J=6.5, 3.9 Hz, 1H), 3.06 (s, 1H), 2.99 (s, 2H), 2.86-2.77(m, 1H), 2.69 (q, J=5.9 Hz, 3H), 2.54 (s, 0H), 2.01-1.79 (m, 3H),1.77-1.52 (m, 2H), 1.46 (s, 1H), 1.16 (s, 1H), 1.07 (d, J=6.4 Hz, 3H),0.82 (d, J=6.4 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 7.57 (d, J=8.0 Hz, 1H),7.31 (d, J=7.6 Hz, 1H), 7.31-7.20 (m, 6H), 7.16 (t, J=2.8 Hz, 1H), 6.99(d, J=8.1 Hz, 1H), 6.52 (t, J=2.7 Hz, 1H), 3.81 (s, 2H), 2.95 (d, J=3.2Hz, 4H).

1H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J=2.0 Hz, 3H), 7.28-7.20 (m,4H), 3.78 (d, J=3.0 Hz, 5H), 3.03-2.92 (m, OH), 2.74 (dt, J=9.9, 2.8 Hz,2H), 2.62-2.49 (m, 6H), 2.46-2.39 (m, 2H), 2.36 (s, 6H), 2.37-2.30 (m,1H), 2.28 (s, 1H), 2.21 (s, 3H), 2.00 (dd, J=20.7, 10.3 Hz, 1H),1.86-1.74 (m, 4H), 1.63 (s, 2H), 1.58 (dd, J=5.1, 2.1 Hz, 1H), 1.57-1.49(m, 2H), 1.45-1.37 (m, 2H), 1.16 (s, 3H), 1.07-0.96 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.87(d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.34-7.16 (m,6H), 3.73 (s, 2H), 2.91 (t, J=6.9 Hz, 2H), 2.82 (t, J=7.0 Hz, 2H), 2.54(s, 0H), 2.48 (s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=7.1 Hz, 4H), 7.21 (t, J=6.8 Hz,1H), 7.05 (d, J=7.7 Hz, 1H), 6.98 (t, J=7.7 Hz, 1H), 6.83 (t, J=7.3 Hz,1H), 6.76 (d, J=8.1 Hz, 1H), 4.29 (d, J=7.2 Hz, 1H), 3.69 (s, 2H), 3.16(dd, J=13.1, 2.1 Hz, 1H), 2.97 (dd, J=13.1, 8.1 Hz, 1H), 2.68 (t, J=6.8Hz, 2H), 2.17 (s, 1H), 1.84 (dp, J=19.9, 7.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J=4.4 Hz, 2H), 8.73 (s, 1H), 8.15(d, J=8.4 Hz, 2H), 8.00 (d, J=8.5 Hz, 3H), 7.71 (dt, J=16.7, 7.1 Hz,2H), 7.60 (t, J=7.8 Hz, 2H), 7.45-7.34 (m, 3H), 7.29 (q, J=7.6 Hz, 8H),7.20 (s, 3H), 3.74 (s, 3H), 3.24 (t, J=7.4 Hz, 3H), 2.86 (q, J=7.8 Hz,4H), 2.54 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (t, J=5.4 Hz, 6H), 7.24-7.13 (m, 1H),7.03 (d, J=8.3 Hz, 1H), 3.69 (s, 2H), 2.71 (dp, J=10.3, 5.1, 4.2 Hz,4H), 2.08 (s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J=4.4 Hz, 2H), 7.26 (s, 1H),7.24 (s, 1H), 3.80 (s, 1H), 2.71 (t, J=6.3 Hz, 1H), 2.49 (t, J=6.4 Hz,1H), 2.34 (t, J=5.7 Hz, 2H), 1.87 (s, 1H), 1.44 (t, J=5.9 Hz, 3H), 1.31(s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=14.6 Hz, 1H), 7.24 (tt, J=7.9,3.6 Hz, 8H), 7.19-7.13 (m, 2H), 6.32 (t, J=7.4 Hz, 1H), 6.18 (t, J=7.3Hz, 2H), 6.04 (t, J=7.5 Hz, 1H), 3.70 (t, J=5.0 Hz, 2H), 3.65 (d, J=2.6Hz, 2H), 2.56 (d, J=15.3 Hz, 3H), 2.47 (s, 7H), 2.23 (dd, J=11.3, 8.3Hz, 1H), 2.14 (dd, J=11.3, 6.5 Hz, 1H), 1.78 (s, 1H), 1.71-1.61 (m, 2H),1.53-1.33 (m, 4H), 1.31-1.14 (m, 3H), 1.03 (d, J=12.8 Hz, 1H), 0.93-0.85(m, 1H), 0.79-0.71 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 4H), 7.16 (t, J=6.8 Hz, 1H),3.70 (s, 2H), 2.47 (td, J=11.3, 5.1 Hz, 3H), 1.81-1.61 (m, 2H),1.63-1.54 (m, 1H), 1.58-1.48 (m, 6H), 1.46-1.38 (m, 2H), 1.38-1.27 (m,1H), 1.04-0.95 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=4.4 Hz, 4H), 7.21 (h, J=4.4 Hz,1H), 3.67 (s, 2H), 2.82 (d, J=7.0 Hz, 1H), 2.82-2.74 (m, 1H), 2.23 (ddd,J=12.8, 7.5, 4.9 Hz, 1H), 2.10-2.01 (m, 1H), 2.04-1.98 (m, 1H),1.74-1.60 (m, 2H), 1.60-1.54 (m, 1H), 1.54-1.49 (m, 1H), 1.52-1.37 (m,3H), 1.27-1.15 (m, 1H), 1.18-1.05 (m, 1H), 1.07-0.94 (m, 1H), 0.94 (d,J=6.9 Hz, 1H), 0.90 (t, J=5.9 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.29-7.20 (m, 4H), 7.16 (dd, J=7.7, 4.6 Hz,1H), 3.73 (s, 2H), 2.54 (s, 1H), 1.86 (dd, J=7.0, 3.9 Hz, 1H), 1.58-1.44(m, 9H), 1.15 (s, 2H), 0.30 (dd, J=7.1, 4.3 Hz, 1H), 0.08 (t, J=4.1 Hz,1H).

1H NMR (400 MHz, DMSO-d6) δ 7.32-7.15 (m, 3H), 3.68 (s, 1H), 2.68-2.54(m, 1H), 2.57-2.51 (m, 1H), 2.25-2.02 (m, 1H), 1.85 (q, J=6.1 Hz, 1H),1.75-1.60 (m, 1H), 1.49 (tdt, J=14.0, 10.5, 5.0 Hz, 2H), 1.36 (tt,J=7.0, 3.6 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.37-7.26 (m, 4H), 7.21 (t, J=7.1 Hz, 1H),7.16-6.97 (m, 5H), 3.77 (d, J=13.7 Hz, 1H), 3.70 (d, J=13.7 Hz, 1H),2.86 (dd, J=9.5, 4.8 Hz, 1H), 2.67 (dq, J=10.2, 5.9, 5.3 Hz, 3H),2.62-2.52 (m, 1H), 2.18 (s, 1H), 1.98-1.88 (m, 1H), 1.76-1.61 (m, 4H).

1H NMR (400 MHz, DMSO-d6) δ 7.35-7.25 (m, 5H), 7.23 (dd, J=16.0, 13.7Hz, 0H), 7.21 (s, 2H), 7.09 (d, J=4.7 Hz, 3H), 7.02 (s, 1H), 3.71 (s,2H), 3.52 (s, 2H), 2.77 (d, J=6.1 Hz, 2H), 2.71-2.52 (m, 6H), 2.03 (s,1H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.17 (m, 4H), 7.16 (ddd, J=8.8, 5.7,3.3 Hz, 1H), 7.03 (q, J=4.4, 3.6 Hz, 3H), 6.97-6.91 (m, 1H), 3.71 (d,J=3.2 Hz, 2H), 3.58 (d, J=14.9 Hz, 1H), 3.03-2.88 (m, 3H), 2.84-2.73 (m,3H), 2.59 (ddt, J=26.1, 12.6, 7.4 Hz, 2H), 2.43 (dd, J=11.6, 5.0 Hz,1H), 1.88 (s, 1H), 0.99 (d, J=6.6 Hz, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.28 (dd, J=8.0, 5.7 Hz, 4H), 7.15-7.08(m, 3H), 6.99 (d, J=5.8 Hz, 1H), 3.88 (d, J=13.6 Hz, 1H), 3.81-3.71 (m,2H), 3.64 (d, J=14.9 Hz, 1H), 2.83 (s, 3H), 2.75 (s, 5H), 2.73-2.65 (m,1H), 2.59 (q, J=11.0, 9.7 Hz, 1H), 1.70 (s, 1H), 1.21 (dt, J=14.0, 8.2Hz, 1H), 0.93 (t, J=7.4 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J=6.5 Hz, 4H), 7.20-7.11 (m, 1H),3.68 (s, 2H), 2.53 (d, J=6.5 Hz, 1H), 1.68 (d, J=12.5 Hz, 5H), 1.33 (t,J=5.8 Hz, 3H), 1.29-1.09 (m, 3H), 0.89 (t, J=11.3 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.83 (dd, J=7.6, 5.0 Hz, 4H), 7.46 (td,J=5.6, 2.5 Hz, 3H), 7.38-7.22 (m, 2H), 4.90 (dd, J=8.7, 3.6 Hz, 1H),3.92-3.80 (m, 2H), 3.03 (dd, J=12.2, 3.7 Hz, 1H), 2.85 (dd, J=12.2, 8.7Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.37-7.26 (m, 4H), 7.27 (s, 1H), 7.21 (t,J=7.0 Hz, 1H), 7.01-6.89 (m, 2H), 6.57-6.46 (m, 2H), 3.76 (d, J=13.7 Hz,1H), 3.69 (d, J=13.7 Hz, 1H), 3.17-3.05 (m, 2H), 2.82 (d, J=9.5 Hz, 1H),2.79 (s, 3H), 2.62 (dd, J=11.9, 4.9 Hz, 1H), 2.55 (d, J=9.3 Hz, 1H),2.16 (s, 1H), 2.08-1.99 (m, 1H), 1.83 (dt, J=12.4, 5.8 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.32-7.21 (m, 4H), 7.16 (t, J=6.9 Hz, 1H),7.06 (d, J=5.1 Hz, 1H), 6.67 (d, J=5.2 Hz, 1H), 3.74 (s, 2H), 3.47 (s,2H), 2.85-2.59 (m, 8H), 2.54 (s, 0H), 1.93 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (q, J=7.9 Hz, 4H), 7.18 (d, J=7.0 Hz,1H), 6.54 (s, 1H), 6.47 (s, 1H), 3.73 (s, 3H), 3.44 (s, 2H), 3.01 (s,7H), 2.76-2.52 (m, 7H), 1.82 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 2H), 7.59 (d, J=7.1 Hz, 2H),7.48-7.36 (m, 3H), 6.96 (t, J=7.7 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 6.71(d, J=8.2 Hz, 1H), 6.51 (t, J=7.3 Hz, 1H), 4.17 (s, 2H), 3.62 (t, J=7.5Hz, 2H), 3.24 (t, J=5.6 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.66 (t, J=6.4Hz, 2H), 1.85 (p, J=6.3, 5.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=4.4 Hz, 4H), 7.21 (q, J=4.5 Hz,1H), 6.79 (d, J=8.2 Hz, 2H), 6.64 (dd, J=7.9, 1.8 Hz, 1H), 5.94 (s, 2H),3.70 (s, 2H), 2.72-2.59 (m, J=4.2 Hz, 4H).

1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=8.4 Hz, 2H), 7.90 (dd, J=12.6,7.2 Hz, 5H), 7.71 (t, J=7.8 Hz, 3H), 7.53 (t, J=7.5 Hz, 2H), 7.44 (d,J=8.6 Hz, 1H), 7.34-7.24 (m, 8H), 7.21 (d, J=7.0 Hz, 2H), 7.13 (s, 1H),5.16 (s, OH), 4.49 (d, J=5.4 Hz, 1H), 3.73 (d, J=4.3 Hz, 3H), 3.08 (t,J=7.1 Hz, 4H), 2.95 (q, J=9.1, 7.1 Hz, 4H), 2.54 (s, 1H), 2.33 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.64-7.57 (m, 1H), 7.43-7.12 (m, 4H), 4.10(s, 1H), 3.13-2.99 (m, 2H).

Example 4: General Compound Syntheses 4

Synthesis of compounds was carried out according to the scheme below:

Amine 1 (0.5 mmol) and compound 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated anddissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield:42-74%.

1H NMR (400 MHz, DMSO-d6) δ 7.32-7.19 (m, 4H), 7.15 (t, J=7.1 Hz, 1H),3.94-3.77 (m, 1H), 3.80-3.70 (m, 2H), 3.65 (dd, J=13.2, 7.1 Hz, 1H),3.63-3.55 (m, 1H), 2.73 (dh, J=10.0, 3.3 Hz, 1H), 1.93 (dtd, J=11.3,6.7, 5.6, 3.4 Hz, 1H), 1.88-1.80 (m, 1H), 1.79 (ddd, J=12.5, 6.1, 3.0Hz, 1H), 1.68-1.31 (m, 3H), 1.05 (dd, J=10.4, 6.2 Hz, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 2H), 3.89 (d, J=15.7 Hz, 4H),3.30 (t, J=11.7 Hz, 2H), 2.83 (t, J=7.7 Hz, 2H), 1.45 (s, 1H), 1.23 (d,J=12.8 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=4.4 Hz, 4H), 7.28-7.17 (m, 1H),3.77 (d, J=13.8 Hz, 1H), 3.70 (d, J=13.9 Hz, 1H), 2.64-2.57 (m, 1H),2.50-2.42 (m, 1H), 2.26-2.11 (m, 4H), 2.06 (s, 3H), 1.97 (s, 1H), 0.92(d, J=6.2 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.27 (dd, J=12.5, 5.6 Hz, 5H), 7.21 (d,J=7.2 Hz, 5H), 7.08 (t, J=6.8 Hz, 4H), 6.83 (d, J=8.1 Hz, 4H), 3.81-3.72(m, 1H), 3.71 (s, 6H), 3.67 (s, 1H), 3.60 (d, J=14.4 Hz, 2H), 3.26 (s,1H), 2.78-2.70 (m, 1H), 2.64 (s, 3H), 1.59 (s, 2H), 1.21 (d, J=6.8 Hz,2H), 1.14 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.2 Hz, 3H), 0.80 (d, J=6.1 Hz,2H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 4H), 7.20-7.12 (m, 1H),3.84-3.73 (m, 2H), 3.64 (d, J=13.4 Hz, 1H), 3.25 (tdd, J=11.7, 5.5, 2.2Hz, 2H), 2.66 (h, J=6.4 Hz, 1H), 1.64 (dqd, J=11.3, 7.3, 3.4 Hz, 1H),1.54-1.42 (m, 2H), 1.36 (dt, J=13.7, 6.8 Hz, 1H), 1.26-1.00 (m, 6H).

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.21 (m, 4H), 7.16 (ddd, J=8.7, 5.3,2.3 Hz, 1H), 3.67 (s, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.32 (h, J=7.9 Hz,1H), 2.02 (ddt, J=15.2, 11.4, 5.1 Hz, 2H), 1.92-1.79 (m, 1H), 1.83-1.73(m, 1H), 1.67-1.49 (m, 4H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (dt, J=14.8, 7.5 Hz, 4H), 7.16 (t,J=7.1 Hz, 1H), 3.82-3.54 (m, 5H), 3.15 (td, J=7.8, 5.8 Hz, 1H),2.62-2.51 (m, 1H), 2.53 (s, 0H), 2.28 (hept, J=7.4 Hz, 1H), 1.95 (dqd,J=19.2, 7.5, 4.5 Hz, 1H), 1.57-1.18 (m, 2H), 1.05 (dd, J=6.2, 3.5 Hz,3H).

1H NMR (400 MHz, DMSO-d6) δ 7.43-7.23 (m, 4H), 7.19 (t, J=7.0 Hz, 1H),3.85 (s, 2H), 1.28 (tt, J=8.3, 5.2 Hz, 1H), 0.38 (ddd, J=14.4, 7.4, 3.0Hz, 3H), 0.23 (d, J=3.8 Hz, 1H), 0.22 (d, J=4.3 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.17 (m, 4H), 7.20-7.11 (m, 1H), 2.53(dd, J=7.6, 4.9 Hz, 1H), 2.40 (dq, J=15.7, 7.8 Hz, 1H), 2.06-1.94 (m,2H), 1.93-1.70 (m, 2H), 1.66-1.50 (m, 3H), 1.34 (dt, J=13.7, 7.0 Hz,1H), 0.98 (d, J=6.2 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.21 (m, 4H), 7.21-7.11 (m, 1H), 3.76(d, J=13.4 Hz, 1H), 3.68 (d, J=13.4 Hz, 1H), 2.69 (p, J=6.3 Hz, 1H),2.30 (s, 5H), 1.36-1.17 (m, 1H), 1.07 (d, J=6.3 Hz, 3H), 0.76-0.64 (m,1H), 0.45-0.36 (m, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.41-7.28 (m, 4H), 7.24 (dt, J=9.0, 2.7Hz, 1H), 3.91 (d, J=13.2 Hz, 1H), 3.70 (d, J=13.2 Hz, 1H), 2.55-2.43 (m,1H), 1.84 (dt, J=13.6, 7.7 Hz, 2H), 1.77-1.66 (m, 1H), 1.65-1.45 (m,4H), 1.24-1.13 (m, 2H), 1.10 (d, J=6.3 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.24 (m, 2H), 7.24 (t, J=7.4 Hz, 2H),7.16 (dq, J=9.4, 4.4, 3.1 Hz, 1H), 3.76 (d, J=13.3 Hz, 1H), 3.65 (d,J=13.3 Hz, 1H), 2.64-2.52 (m, 1H), 1.87 (dp, J=15.5, 7.7, 6.9 Hz, 1H),1.71 (qd, J=10.1, 9.5, 3.7 Hz, 2H), 1.65-1.40 (m, 5H), 1.25 (dt, J=13.5,6.9 Hz, 1H), 1.10-0.97 (m, 4H).

1H NMR (400 MHz, Chloroform-d) δ 7.37-7.21 (m, 3H), 3.89 (t, J=7.7 Hz,1H), 3.84 (td, J=8.2, 4.7 Hz, 1H), 3.79 (s, 2H), 3.73 (q, J=7.8 Hz, 1H),3.33 (t, J=7.8 Hz, 1H), 2.65 (q, J=7.1 Hz, 2H), 2.24 (p, J=7.5 Hz, 1H),2.09-1.96 (m, 1H), 1.65-1.44 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.32-7.25 (m, 4H), 7.20 (d,J=7.7 Hz, 2H), 3.75 (s, 3H), 3.72 (q, J=13.5 Hz, 2H), 2.75-2.63 (m, 1H),2.58-2.50 (m, 2H), 2.34 (dd, J=14.1, 7.0 Hz, 1H), 0.94 (d, J=6.2 Hz,3H).

1H NMR (400 MHz, Chloroform-d) δ 7.32 (dd, J=4.4, 2.2 Hz, 6H), 7.27-7.20(m, 2H), 3.86-3.74 (m, 1H), 3.78 (s, 2H), 2.65-2.44 (m, 2H), 2.33 (dd,J=11.5, 6.9 Hz, 1H), 2.17 (d, J=12.2 Hz, 2H), 2.05 (s, 1H), 1.65-1.59(m, 3H), 1.45-1.35 (m, 1H), 1.34-1.10 (m, 3H), 1.04 (dd, J=22.7, 11.6Hz, 2H), 0.66-0.57 (m, 0H).

1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J=5.8 Hz, 4H), 7.23-7.17 (m, 1H),6.84 (d, J=8.2 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.70 (dd, J=8.2, 2.0 Hz,1H), 3.74-3.64 (m, 9H), 2.80 (q, J=7.0 Hz, 1H), 2.59 (qd, J=11.4, 7.1Hz, 2H), 2.53 (s, 1H), 1.76 (s, 1H), 1.17 (d, J=6.9 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J=2.3 Hz, 1H), 7.27 (d, J=4.5 Hz,4H), 7.20 (q, J=5.3, 4.7 Hz, 1H), 5.97 (d, J=2.3 Hz, 1H), 4.39 (p, J=6.7Hz, 1H), 3.75 (d, J=13.5 Hz, 1H), 3.67 (d, J=13.5 Hz, 1H), 2.80 (q,J=6.3 Hz, 1H), 2.65 (dd, J=14.0, 6.1 Hz, 1H), 1.36 (d, J=6.7 Hz, 6H),1.32 (s, 0H), 0.98 (d, J=6.2 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.17 (m, 10H), 7.21-7.16 (m, 1H), 3.77(d, J=6.9 Hz, 2H), 2.79 (s, 2H), 1.81 (t, J=7.0 Hz, 1H), 0.52 (d, J=11.8Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz,2H), 7.20 (t, J=7.2 Hz, 1H), 7.10 (d, J=8.1 Hz, 2H), 6.83 (d, J=8.1 Hz,2H), 3.73 (d, J=9.7 Hz, 5H), 2.64 (s, 2H), 1.43 (s, 1H), 1.00 (s, 5H).

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.21 (m, 4H), 7.19 (s, 1H), 7.15 (tt,J=5.6, 2.9 Hz, 1H), 3.79-3.69 (m, 1H), 3.61 (d, J=13.5 Hz, 1H), 3.07 (s,3H), 2.76 (h, J=6.2 Hz, 1H), 2.04 (p, J=10.6 Hz, 2H), 1.88-1.77 (m, 3H),1.77-1.63 (m, 1H), 1.62-1.48 (m, 2H), 1.04 (d, J=6.2 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (q, J=7.8, 7.3 Hz, 5H), 7.23 (d, J=13.1Hz, 2H), 7.19 (s, 1H), 6.84 (d, J=8.3 Hz, 2H), 6.77 (s, 1H), 6.69 (d,J=8.9 Hz, 2H), 3.78 (d, J=14.0 Hz, 1H), 3.70 (d, J=6.9 Hz, 9H), 3.61 (d,J=15.6 Hz, 1H), 2.66 (s, 3H), 2.54 (s, 1H), 1.66 (s, 2H), 1.22 (d, J=5.9Hz, 2H), 1.14 (d, J=6.9 Hz, 2H), 0.89 (t, J=7.4 Hz, 2H), 0.83 (d, J=5.3Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.33-7.12 (m, 8H), 7.10-6.98 (m, 4H), 3.75(s, 2H), 2.64 (dd, J=12.2, 6.2 Hz, 1H), 2.57-2.47 (m, 2H), 1.70 (dt,J=9.2, 4.9 Hz, 1H), 1.30-1.19 (m, 1H), 0.83 (ddd, J=13.9, 9.5, 4.9 Hz,2H).

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.19 (m, 4H), 7.15 (t, J=7.1 Hz, 1H),3.56 (t, J=4.6 Hz, 4H), 3.00 (s, 2H), 2.54 (dd, J=5.6, 3.4 Hz, 4H), 2.42(s, 1H), 2.27 (s, 2H), 1.47 (s, 1H), 1.05 (s, 5H).

1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=2.4 Hz, 1H), 7.50 (dd, J=8.5, 2.4Hz, 1H), 7.28 (d, J=4.5 Hz, 4H), 7.20 (q, J=4.4 Hz, 1H), 6.72 (d, J=8.4Hz, 1H), 3.78 (d, J=23.2 Hz, 4H), 3.70 (d, J=13.6 Hz, 1H), 2.71 (ddt,J=18.8, 13.3, 6.0 Hz, 2H), 2.45 (dd, J=13.2, 6.7 Hz, 1H), 1.87 (s, 1H),0.92 (d, J=6.1 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (ddt, J=11.3, 8.2, 5.1 Hz, 4H), 7.20(d, J=7.5 Hz, 1H), 3.83-3.65 (m, 2H), 3.20 (t, J=6.9 Hz, 1H), 3.12 (s,1H), 2.54 (s, 1H), 2.17-2.01 (m, 1H), 2.01-1.81 (m, 1H), 1.13-0.95 (m,4H), 0.96 (s, 1H), 0.35 (ddq, J=26.9, 8.7, 5.1 Hz, 1H), 0.13 (dddd,J=26.6, 18.0, 8.5, 4.4 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=4.9 Hz, 1H), 7.67 (td, J=7.6, 2.0Hz, 1H), 7.34-7.21 (m, 5H), 7.19 (dd, J=10.7, 4.7 Hz, 3H), 3.76 (d,J=13.6 Hz, 1H), 3.68 (d, J=13.8 Hz, 1H), 3.00-2.92 (m, 2H), 2.90 (d,J=7.0 Hz, 1H), 2.64 (dd, J=12.7, 6.7 Hz, 1H), 2.07 (s, 1H), 0.96 (d,J=6.0 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.38-7.24 (m, 4H), 7.21 (t, J=7.1 Hz, 1H),7.08 (ddd, J=14.2, 7.1, 2.8 Hz, 3H), 7.02 (d, J=8.9 Hz, 1H), 3.76 (dd,J=17.5, 3.8 Hz, 2H), 2.54 (s, 1H), 2.13 (dt, J=14.5, 7.2 Hz, 1H), 2.02(s, 1H), 1.69 (dt, J=8.6, 5.1 Hz, 1H), 1.11 (t, J=5.8 Hz, 3H), 1.00-0.84(m, 2H), 0.77 (ddt, J=20.2, 9.0, 5.0 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.06 (s, 2H), 7.66-7.59 (m,2H), 7.47-7.36 (m, 3H), 4.06 (d, J=13.1 Hz, 1H), 3.97 (d, J=13.0 Hz,1H), 2.89 (dt, J=13.0, 6.4 Hz, 1H), 1.35 (d, J=6.4 Hz, 3H), 1.08 (d,J=17.4 Hz, 6H), 0.95 (s, 3H), 0.88 (s, 3H), 0.54 (d, J=10.6 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 3H), 8.88 (s, 3H), 7.63 (dd, J=6.5,3.2 Hz, 5H), 7.42 (d, J=6.5 Hz, 8H), 4.24-4.15 (m, 3H), 4.09 (dq,J=13.8, 7.5, 6.8 Hz, 3H), 3.16 (s, 1H), 2.97 (s, 1H), 2.54 (s, 1H), 2.04(s, 3H), 1.87 (dt, J=11.8, 6.0 Hz, 2H), 1.69 (d, J=12.7 Hz, 2H), 1.60(d, J=12.5 Hz, 3H), 1.48 (s, 2H), 1.41 (s, 2H), 1.41 (d, J=12.6 Hz, 2H),1.29-1.20 (m, 1H), 1.23-1.15 (m, 7H), 1.03 (td, J=12.7, 4.7 Hz, 1H),0.97 (s, 2H), 0.95 (s, 2H), 0.93 (d, J=6.6 Hz, 0H), 0.86 (dq, J=13.5,6.6 Hz, 10H), 0.64 (tq, J=12.2, 7.3, 6.8 Hz, 3H), 0.50 (q, J=12.0 Hz,1H).

1H NMR (400 MHz, DMSO-d6) δ 7.57-7.46 (m, 5H), 7.26 (d, J=4.5 Hz, 4H),7.19 (q, J=4.5 Hz, 1H), 3.77 (d, J=13.7 Hz, 1H), 3.70 (d, J=13.8 Hz,1H), 2.82 (ddd, J=18.5, 12.6, 6.1 Hz, 2H), 2.62 (dd, J=12.2, 5.7 Hz,1H), 2.22 (s, 1H), 0.95 (d, J=5.8 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J=4.9 Hz, 2H), 7.32 (t, J=4.9 Hz,1H), 7.26 (d, J=5.5 Hz, 4H), 7.19 (d, J=5.5 Hz, 1H), 3.79-3.65 (m, 2H),3.11 (ddd, J=22.8, 12.9, 6.2 Hz, 2H), 2.79 (dd, J=12.9, 6.7 Hz, 1H),2.54 (s, 1H), 2.13 (s, 1H), 1.00 (d, J=6.1 Hz, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.36-7.19 (m, 6H), 3.90-3.79 (m, 4H),3.77 (s, 4H), 3.34 (ddd, J=11.0, 9.0, 4.3 Hz, 2H), 3.05 (t, J=10.6 Hz,2H), 2.71-2.56 (m, 4H), 1.88-1.78 (m, 2H), 1.72-1.53 (m, 4H), 1.46-1.23(m, 3H), 1.23-1.07 (m, 1H), 1.13 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.27 (d, J=4.4 Hz, 4H), 7.19(dt, J=8.9, 4.3 Hz, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.75 (d, J=13.6 Hz,1H), 3.69 (d, J=13.6 Hz, 1H), 3.00 (p, J=6.4 Hz, 1H), 2.83 (dd, J=13.2,6.2 Hz, 1H), 2.62-2.52 (m, 1H), 2.09 (s, 1H), 0.97 (d, J=6.3 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=5.2 Hz, 1H), 7.28 (d, J=4.4 Hz,4H), 7.20 (q, J=4.4 Hz, 1H), 6.82-6.76 (m, 1H), 6.60 (s, 1H), 3.81 (s,3H), 3.76 (d, J=14.1 Hz, 1H), 3.70 (d, J=13.8 Hz, 1H), 2.83 (q, J=6.3Hz, 1H), 2.76 (dd, J=12.9, 5.8 Hz, 1H), 2.54 (s, 1H), 2.46 (dd, J=12.8,7.0 Hz, 1H), 1.91 (s, 1H), 0.93 (d, J=6.1 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.38-7.15 (m, 7H), 7.09 (dt, J=22.5, 6.8 Hz,3H), 3.79 (d, J=6.3 Hz, 1H), 3.74 (d, J=5.1 Hz, 1H), 2.13 (dq, J=13.9,6.8 Hz, 1H), 2.04 (s, 1H), 1.71 (ddt, J=35.4, 9.4, 5.0 Hz, 1H), 1.11 (t,J=7.0 Hz, 3H), 1.03-0.88 (m, 1H), 0.92-0.69 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.35-7.24 (m, 4H), 7.19 (t, J=7.2 Hz, 1H),3.81 (d, J=13.7 Hz, 1H), 3.54 (d, J=13.7 Hz, 1H), 2.54 (s, 2H), 2.03 (s,1H), 1.51-1.43 (m, 8H), 1.40 (s, 2H), 1.31 (s, 1H), 1.26 (s, 4H), 0.86(d, J=6.5 Hz, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.39-7.28 (m, 4H), 7.28-7.19 (m, 1H),5.34 (d, J=3.1 Hz, 1H), 3.89-3.77 (m, 2H), 3.17 (dd, J=5.2, 2.8 Hz, 1H),2.16 (p, J=6.8 Hz, 1H), 2.07-1.94 (m, 2H), 1.93-1.81 (m, 1H), 1.65-1.52(m, 2H), 1.37 (s, 2H), 0.99 (d, J=6.8 Hz, 5H), 0.98-0.83 (m, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 8H), 7.15 (t, J=7.1 Hz, 2H),3.81 (d, J=13.2 Hz, 1H), 3.72 (d, J=13.3 Hz, 1H), 3.61 (dd, J=27.8, 13.3Hz, 2H), 3.00 (s, 1H), 2.72-2.58 (m, 2H), 1.73-1.62 (m, 10H), 1.54 (d,J=12.7 Hz, 1H), 1.39-1.26 (m, 2H), 1.21 (s, 3H), 1.14 (dddd, J=21.6,16.3, 10.8, 7.7 Hz, 6H), 1.06-0.84 (m, 8H), 0.80 (dd, J=21.9, 6.6 Hz,6H).

1H NMR (400 MHz, DMSO-d6) δ 7.35-7.24 (m, 2H), 3.69-3.61 (m, 2H),3.60-3.53 (m, 1H), 2.79 (q, J=5.4, 4.5 Hz, 2H), 2.46 (s, 1H), 1.74 (p,J=5.9 Hz, 1H), 1.65 (s, 1H), 1.01 (s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (ddt, J=11.3, 8.2, 5.1 Hz, 4H), 7.20(d, J=7.5 Hz, 1H), 3.83-3.65 (m, 2H), 3.20 (t, J=6.9 Hz, 1H), 3.12 (s,1H), 2.54 (s, 1H), 2.17-2.01 (m, 1H), 2.01-1.81 (m, 1H), 1.13-0.95 (m,4H), 0.96 (s, 1H), 0.35 (ddq, J=26.9, 8.7, 5.1 Hz, 1H), 0.13 (dddd,J=26.6, 18.0, 8.5, 4.4 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.32-7.11 (m, 3H), 3.63 (s, 1H), 1.74 (ddd,J=13.2, 7.3, 3.2 Hz, 1H), 1.70-1.52 (m, 3H), 1.45 (q, J=11.5, 10.5 Hz,2H), 1.37-1.22 (m, 2H), 1.08 (s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J=7.8 Hz, 2H), 7.44 (d, J=7.9 Hz,2H), 7.35 (d, J=7.4 Hz, 2H), 7.29 (t, J=7.5 Hz, 2H), 7.20 (t, J=7.2 Hz,1H), 3.76 (d, J=7.5 Hz, 2H), 2.80 (s, 2H), 1.60 (t, J=7.6 Hz, 1H), 1.03(s, 5H).

1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J=7.9 Hz, 2H), 7.52 (d, J=7.8 Hz,2H), 7.26 (d, J=4.4 Hz, 4H), 7.19 (td, J=6.7, 5.0, 3.0 Hz, 1H), 3.77 (d,J=4.9 Hz, 2H), 2.86 (s, 2H), 1.89 (s, 1H), 0.56 (dt, J=11.5, 2.1 Hz,3H).

1H NMR (400 MHz, DMSO-d6) δ 7.35-7.22 (m, 6H), 7.26-7.15 (m, 1H), 7.11(t, J=8.9 Hz, 2H), 3.75 (d, J=4.0 Hz, 2H), 2.76 (s, 2H), 2.54 (s, 0H),1.83 (s, 1H, 0.52 (dt, J=14.7, 2.0 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.35-7.25 (m, 4H), 7.24-7.15 (m, 1H), 3.69(s, 2H), 2.54 (s, 0H), 2.21 (s, 2H), 1.78 (s, 1H), 1.50-1.35 (m, 6H),1.36 (s, 3H), 1.27-1.16 (m, 2H), 0.83 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.23 (m, 4H), 7.23 (d, J=7.6 Hz, 2H),7.20-7.11 (m, 1H), 3.77-3.61 (m, 3H), 2.53 (d, J=4.2 Hz, 1H), 1.73 (s,1H), 1.70 (dddt, J=22.8, 9.6, 6.3, 3.0 Hz, 3H), 1.62-1.39 (m, 6H),1.42-1.33 (m, 1H), 1.36-1.12 (m, 2H), 0.92 (d, J=6.4 Hz, 4H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=6.6 Hz, 4H), 7.20 (s, 1H), 3.66(s, 2H), 2.54 (s, 1H), 2.45 (dd, J=11.4, 5.7 Hz, 1H), 2.25 (dd, J=11.5,7.6 Hz, 1H), 1.86 (s, 1H), 1.67 (d, J=12.4 Hz, 2H), 1.60 (d, J=11.8 Hz,1H), 1.51 (d, J=11.9 Hz, 2H), 1.46-1.36 (m, 1H), 1.29 (dt, J=11.7, 3.8Hz, 1H), 1.22-1.02 (m, 2H), 1.06-0.92 (m, 1H), 0.81 (d, J=6.9 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.30-7.20 (m, 8H), 7.16 (t, J=6.8 Hz, 2H),2.53 (d, J=7.0 Hz, 3H), 1.88-1.74 (m, 2H), 1.78-1.67 (m, 4H), 1.65-1.51(m, 3H), 1.55 s, 3H), 1.47 (dq, J=14.5, 7.3 Hz, 7H), 1.14-1.01 (m, 4H).

1H NMR (400 MHz, Chloroform-d) δ 7.29 (s, 8H), 3.48 (s, 1H) 1.25 (s,1H).

1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 2H), 8.82 (s, 2H), 7.64-7.57 (m,3H), 7.48-7.36 (m, 5H), 4.14 (d, J=16.7 Hz, 4H), 2.54 (s, 2H), 2.38 (s,2H), 1.33 (d, J=6.7 Hz, 4H), 1.08 (s, 4H), 0.55 (ddt, J=19.4, 10.4, 5.2Hz, 3H), 0.34 (dq, J=9.7, 5.8, 5.4 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.32-7.21 (m, 4H), 7.17 (t, J=6.9 Hz, 1H),4.10-4.05 (m, 1H), 3.76-3.64 (m, 2H), 3.25 (s, 1H), 2.54 (dd, J=11.4,3.0 Hz, 1H), 2.41 (dd, J=11.6, 8.6 Hz, 1H), 1.79 (d, J=12.7 Hz, 1H),1.70 (s, 3H), 1.67-1.54 (m, 2H), 1.24 (s, 1H), 1.20-1.14 (m, 2H), 1.13(d, J=9.2 Hz, 1H), 1.06-0.89 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.22 (dd, J=8.8, 5.7 Hz, 6H), 7.18-7.09 (m,4H), 4.21 (d, J=5.5 Hz, 1H), 3.41-3.32 (m, 1H), 3.24 (dt, J=10.6, 5.0Hz, 1H), 3.02 (s, 2H), 2.79-2.66 (m, 2H), 2.65 (dd, J=12.8, 7.1 Hz, 1H),1.76 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.26-7.11 (m, 10H), 4.22 (s, 1H), 3.75 (s,2H), 3.36 (s, 1H), 2.79-2.62 (m, 3H), 1.76 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=4.4 Hz, 6H), 7.18 (s, 3H),7.25-7.07 (m, 7H), 6.98 (d, J=7.2 Hz, 3H), 3.75 (d, J=7.3 Hz, 2H),3.68-3.55 (m, 2H), 3.42-3.29 (m, 3H), 3.25 (s, 1H), 2.95 (s, 1H), 2.28(s, 2H), 2.17 (ddd, J=21.2, 10.2, 4.2 Hz, 4H), 1.89 (t, J=9.2 Hz, 1H),1.68 (s, 1H), 1.24 (s, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.34 (s, 1H), 7.26 (s, 1H), 4.03 (d,J=13.3 Hz, 1H), 3.82 (d, J=13.3 Hz, 1H), 3.09 (s, 1H), 1.69 (d, J=13.0Hz, 1H), 1.46 (d, J=11.4 Hz, 1H), 1.42 (s, 3H), 1.29 (s, 1H), 1.13 (d,J=10.6 Hz, 2H), 0.95 (d, J=11.6 Hz, 1H), 0.73 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J=6.6 Hz, 4H), 7.17 (d, J=6.9 Hz,1H), 3.69 (s, 2H), 1.73 (s, 1H), 1.54 (s, 1H), 1.42 (s, 2H), 1.34 (q,J=8.1 Hz, 2H), 1.30-1.22 (m, 1H), 0.89 (d, J=6.2 Hz, 1H), 0.83 (d, J=7.1Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.31 (s, 3H), 7.30-7.18 (m, 2H), 3.77(s, 3H), 2.62 (q, J=7.9 Hz, 3H), 1.75-1.59 (m, 1H), 1.66 (s, 2H),1.57-1.12 (m, 7H), 1.09 (p, J=5.8, 5.2 Hz, 1H), 0.85 (dd, J=10.5, 6.7Hz, 4H).

1H NMR (400 MHz,) δ 11.47 (d, J=4.0 Hz, 10H), 7.48 (d, J=7.6 Hz, 2H),7.44 (t, J=7.6 Hz, 3H), 4.52 (dd, J=13.3, 4.1 Hz, 1H), 4.44-4.36 (m,1H), 4.25-4.19 (m, 1H), 1.93 (t, J=6.9 Hz, 2H), 1.74 (d, J=12.7 Hz, 3H),1.68 (s, 2H), 1.61 (d, J=4.6 Hz, 0H), 1.44 (s, 2H), 1.25 (s, 1H), 1.16(s, 3H), 0.93 (s, 2H).

Example 5: General Compound Syntheses 5

Step A

Compound 1 (0.22 ml) was added to a suspension of 2-OH-benzaldehyde 2(0.17 g) and potassium carbonate (0.20 g) in DMF (5 ml), and the mixturewas stirred at 90° C. for 1 hour. The mixture was allowed to cool toroom temperature, and neutralized with 1N hydrochloric acid. Afterextraction with ethyl acetate, the organic layer was washed withsaturated salt water, dried over anhydrous sodium sulfate, andconcentrated. The concentrate was purified by silica gel columnchromatography (n-hexane/ethyl acetate=4/1). Yield: 23-39%.

Step B

Amine 4 (0.5 mmol), aldehyde 3 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated anddissolved in 0.5 ml of DMSO. The residue 5 was purified using HPLC.Yield: 23-38%.

1H NMR (400 MHz, Chloroform-d) δ 7.24 (d, J=17.8 Hz, 1H), 6.97 (t, J=7.5Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 5.97 (s, 1H), 5.42 (s, 1H), 4.97 (dq,J=9.4, 4.7 Hz, 1H), 4.17 (qd, J=10.2, 4.3 Hz, 2H), 3.79 (d, J=6.2 Hz,3H), 3.62 (dd, J=8.7, 5.6 Hz, 1H), 3.56 (s, 1H), 2.65 (t, J=7.0 Hz, 2H),2.13 (t, J=7.2 Hz, 2H), 1.95 (s, 2H), 1.80 (d, J=6.6 Hz, 2H), 1.54 (td,J=11.6, 5.9 Hz, 4H). Compound B377 was synthesized in accord with thisprocedure.

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=7.4 Hz, 1H), 7.19 (t, J=7.8 Hz,1H), 6.98-6.87 (m, 2H), 4.84-4.78 (m, 1H), 4.16 (dd, J=8.8, 5.0 Hz, 1H),4.08 (dd, J=11.1, 5.2 Hz, 1H), 3.75-3.64 (m, 2H), 3.58 (dd, J=14.2, 6.6Hz, 1H), 3.43 (t, J=7.7 Hz, 1H), 2.55 (q, J=6.3 Hz, 4H), 1.57 (d, J=11.5Hz, 5H), 1.48 (d, J=12.9 Hz, 1H), 1.27 (d, J=12.0 Hz, 2H), 1.18-1.09 (m,1H), 1.04 (s, 2H), 0.95 (d, J=6.1 Hz, 3H), 0.76 (s, 3H), 0.72-0.62 (m,3H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=7.4 Hz, 1H), 7.21 (t, J=7.8 Hz,1H), 7.00-6.88 (m, 2H), 5.35 (s, 1H), 4.90-4.82 (m, 1H), 4.19 (dd,J=10.8, 3.0 Hz, 1H), 4.10 (dd, J=10.8, 4.4 Hz, 1H), 3.71 (t, J=9.0 Hz,1H), 3.64 (s, 2H), 3.46 (dd, J=8.6, 6.1 Hz, 1H), 3.22 (q, J=7.2 Hz, 2H),2.53 (d, J=6.2 Hz, 2H), 2.04 (t, J=7.2 Hz, 2H), 1.92 (s, 2H), 1.81 (d,J=6.6 Hz, 2H), 1.51 (ddt, J=19.8, 13.8, 6.5 Hz, 5H), 1.09 (t, J=7.2 Hz,3H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=7.4 Hz, 1H), 7.20 (t, J=7.8 Hz,1H), 6.96 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 4.87 (d, J=7.0 Hz,1H), 4.19 (q, J=6.4, 3.5 Hz, 1H), 4.15-4.04 (m, 1H), 3.71 (dd, J=14.0,8.9 Hz, 2H), 3.59 (dd, J=14.3, 8.8 Hz, 1H), 3.52-3.41 (m, 1H), 3.22 (q,J=7.4 Hz, 2H), 2.55 (d, J=7.6 Hz, 2H), 1.58 (d, J=11.3 Hz, 5H), 1.47 (t,J=15.1 Hz, 1H), 1.29 (dd, J=11.2, 5.4 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H),1.07-0.92 (m, 3H), 0.77 (t, J=13.9 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=7.4 Hz, 1H), 7.20 (t, J=7.8 Hz,1H), 6.93 (dd, J=17.2, 8.3 Hz, 2H), 5.35 (s, 1H), 4.80 (dt, J=9.2, 4.5Hz, 1H), 4.16 (dd, J=11.0, 3.0 Hz, 1H), 4.07 (dd, J=11.0, 4.5 Hz, 1H),3.68 (t, J=9.0 Hz, 1H), 3.62 (s, 2H), 3.42 (dd, J=8.6, 6.0 Hz, 1H),2.60-2.47 (m, 4H), 2.04 (t, J=7.4 Hz, 2H), 1.92 (s, 2H), 1.81 (d, J=6.6Hz, 2H), 1.67 (s, 0H), 1.50 (dt, J=19.6, 6.6 Hz, 4H), 0.77-0.65 (m, 4H).

1H NMR (400 MHz, Chloroform-d) δ 6.97 (t, J=7.3 Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 5.43 (s, 1H), 4.84 (s, 1H), 4.16 (s, 2H), 3.80-3.69 (m, 2H),3.60-3.52 (m, 1H), 2.94 (s, 3H), 2.66 (t, J=7.0 Hz, 1H), 2.15 (s, 2H),1.97 (s, 2H), 1.85 (s, 2H), 1.25 (s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.29 (s, 1H), 7.22 (d, J=8.0 Hz, 1H),6.97 (t, J=7.3 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.85 (s, 1H), 4.17 (dd,J=8.5, 5.0 Hz, 1H), 3.83 (d, J=13.3 Hz, 1H), 3.78-3.66 (m, 2H),3.60-3.52 (m, 1H), 2.93 (s, 3H), 2.70 (d, J=6.7 Hz, 1H), 1.35 (s, 3H),1.15 (d, J=10.5 Hz, 6H), 1.06 (d, J=6.3 Hz, 3H), 0.84 (s, 3H).

Example 6: General Compound Syntheses 6

Amine 1 (0.25 mmol) and aldehyde 2 (0.23 mmol) were dissolved in 0.3 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄(0.25 mmol) was added and stirred for 4 hours. The mixture was heatedfor 2 hours at 60° C., 3 ml of methanol and 0.1 g of C-18chromatographic phase were added, stirred for 2 hours, filtered,evaporated and dissolved in 0.25 ml of DMSO. The residue was purifiedusing HPLC. Yield: 32-47%.

1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J=8.0 Hz, 1H), 7.93-7.86 (m, 1H),7.76 (d, J=8.0 Hz, 1H), 7.56-7.46 (m, 2H), 7.49-7.37 (m, 1H), 7.36 (d,J=6.9 Hz, 1H), 7.35-7.24 (m, 4H), 7.20 (t, J=7.0 Hz, 1H), 3.74 (s, 2H),3.21 (t, J=7.6 Hz, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.32 (s, 1H).

1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.2Hz, 1H), 7.50 (p, J=6.9 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 7.17 (d, J=7.7Hz, 2H), 7.10 (d, J=7.7 Hz, 2H), 6.73 (d, J=7.8 Hz, 1H), 3.98 (s, 3H),3.78 (s, 2H), 3.22 (t, J=7.2 Hz, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.32 (s,3H).

1H NMR (400 MHz, DMSO-d6) δ 8.08-8.01 (m, 1H), 7.94-7.87 (m, 1H), 7.79(d, J=8.1 Hz, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.48 (dq, J=7.2, 3.6, 2.9 Hz,3H), 7.31 (dt, J=14.8, 7.5 Hz, 4H), 7.21 (t, J=7.1 Hz, 1H), 5.45 (s,2H), 5.43 (d, J=3.8 Hz, 0H), 3.79 (s, 2H), 2.86-2.78 (m, 1H), 2.69 (dd,J=12.2, 7.8 Hz, 1H), 2.31 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.89-7.71 (m, 4H), 7.66 (s, 1H), 7.51-7.39(m, 3H), 7.34 (d, J=9.0 Hz, 1H), 7.27 (d, J=6.6 Hz, 4H), 7.20 (d, J=6.5Hz, 1H), 3.80 (d, J=13.6 Hz, 1H), 3.74 (d, J=13.8 Hz, 1H), 2.94 (ddd,J=26.2, 12.3, 5.7 Hz, 2H), 2.64 (dd, J=12.7, 7.0 Hz, 1H), 1.94 (s, 1H),0.98 (d, J=6.1 Hz, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.76 (dd, J=7.4, 1.9 Hz, 1H), 7.70 (d,J=8.3 Hz, 1H), 7.48-7.23 (m, 9H), 4.13 (s, 1H), 4.02 (d, J=13.3 Hz, 1H),3.93 (d, J=13.3 Hz, 1H), 3.04 (d, J=16.3 Hz, 1H), 2.19 (dd, J=9.8, 4.8Hz, 1H).

Example 7: General Compound Syntheses 7

Step A:

A solution of 2-hydroxybenzaldehyde 1 (5.0 mmol, 1.0 equiv), K₂CO₃ (7.5mmol, 1.5 equiv), compound 2 (5.0 mmol, 1.0 equiv) in CH₃CN (50 mL) wasrefluxed and monitored by TLC. After completion of the reaction, thesolution was cooled; solvent was evaporated under reduced pressure. Theresidue was poured into water (30 mL) and extracted with ethyl acetate(3×30 mL). The organic layer was washed with brine and dried overanhydrous MgSO₄. Filtration of MgSO₄ and evaporation of solvent undervacuum gave the crude product. The residue obtained was purified byusing HPLC to obtain the corresponding compound 3. Yield: 34-58%.

Step B:

Aldehyde 3 (0.55 mmol), amine 4 (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated andoptionally dissolved in 0.5 mL of DMSO. The residue was purified usingHPLC. Yield: 24-47%.

1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.19 (t, J=8.0 Hz, 2H),6.93-6.84 (m, 2H), 4.51 (s, 2H), 3.78 (d, J=12.0 Hz, 1H), 3.65 (d,J=12.1 Hz, 1H), 2.71 (d, J=5.8 Hz, 2H), 2.66 (d, J=4.6 Hz, 3H), 2.54 (s,1H), 1.67 (d, J=15.3 Hz, 5H), 1.35 (s, 1H), 1.20 (dd, J=22.0, 9.6 Hz,2H), 1.05 (d, J=6.2 Hz, 3H), 0.86 (d, J=12.3 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=6.8 Hz, 1H), 7.98 (s, 1H), 7.51(d, J=9.0 Hz, 1H), 7.21 (ddd, J=28.6, 15.1, 7.8 Hz, 4H), 6.88 (t, J=6.9Hz, 2H), 5.22 (d, J=2.6 Hz, 2H), 3.73 (d, J=13.6 Hz, 1H), 3.61 (d,J=13.8 Hz, 1H), 2.54 (s, 0H), 1.71 (s, 1H), 1.50 (d, J=11.8 Hz, 4H),1.43 (s, 1H), 1.24 (s, 2H), 1.01 (d, J=16.2 Hz, 5H), 0.91 (d, J=6.0 Hz,2H), 0.74-0.64 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J=7.2 Hz, 1H), 7.17 (t, J=7.8 Hz,11H), 6.94 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.4 Hz, 1H), 4.00 (t, J=5.9 Hz,2H), 3.71 (d, J=13.7 Hz, 1H), 3.58 (d, J=14.2 Hz, 1H), 2.79 (t, J=5.7Hz, 2H), 2.60-2.52 (m, 4H), 1.61 (d, J=16.9 Hz, 3H), 1.56 (s, 2H), 1.49(d, J=13.0 Hz, 1H), 1.28 (s, 2H), 1.17 (d, J=12.1 Hz, 1H), 1.12 (s, 2H),1.07-0.92 (m, 8H), 0.81 (s, 1H), 0.80-0.71 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.21-7.09 (m, 1H), 6.83 (s, 1H), 4.08 (t,J=5.6 Hz, 1H), 3.60 (t, J=4.7 Hz, 2H), 2.75 (t, J=5.8 Hz, 1H), 1.64 (s,2H), 1.29 (s, 1H), 1.16 (s, 2H), 0.98 (d, J=6.1 Hz, 1H), 0.82 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.21-7.11 (m, 2H), 6.87 (d, J=8.0 Hz, 1H),6.81 (s, 1H), 4.06 (s, 2H), 3.73 (d, J=13.4 Hz, 1H), 3.61 (s, 4H), 2.54(s, 1H), 1.92 (s, 2H), 1.63 (s, 6H), 1.29 (s, 4H), 1.16 (s, 4H), 1.07(s, 1H), 0.99 (d, J=6.1 Hz, 3H), 0.83 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (dd, J=7.4, 4.9 Hz, 2H), 7.22 (t, J=7.8Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 6.76 (d, J=3.5Hz, 1H), 5.17 (d, J=3.5 Hz, 2H), 3.80 (s, 3H), 3.68 (d, J=13.8 Hz, 1H),3.59 (d, J=13.8 Hz, 1H), 2.51 (s, 1H), 1.56 (s, 5H), 1.47 (d, J=12.7 Hz,1H), 1.24 (s, 2H), 1.11 (q, J=10.6, 9.2 Hz, 2H), 0.91 (d, J=6.1 Hz, 3H),0.75 (q, J=11.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=5.0 Hz, 2H), 7.40 (d, J=5.4 Hz,2H), 7.27 (d, J=7.4 Hz, 1H), 7.15 (t, J=8.2 Hz, 1H), 6.94-6.84 (m, 2H),5.16 (s, 2H), 3.82 (d, J=13.5 Hz, 1H), 3.71 (d, J=13.5 Hz, 1H),2.69-2.61 (m, 1H), 1.60 (q, J=14.9, 12.0 Hz, 6H), 1.28 (q, J=7.8 Hz,3H), 1.12 (s, 5H), 1.00 (d, J=6.0 Hz, 3H), 0.86-0.75 (m, 2H).

1H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.30-7.21 (m, 3H), 6.96(t, J=7.4 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 3.90 (d, J=12.0Hz, 1H), 3.73 (d, J=12.0 Hz, 1H), 3.15 (q, J=5.8 Hz, 2H), 2.83-2.75 (m,1H), 1.39 (dd, J=13.0, 6.5 Hz, 1H), 1.30 (s, 1H), 1.16 (s, 4H), 1.10 (d,J=6.1 Hz, 3H), 0.88 (s, 3H), 0.85 (d, J=2.3 Hz, 0H), 0.41 (d, J=7.7 Hz,2H), 0.13 (d, J=5.2 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.15 (t, J=7.7 Hz, 1H), 6.97 (t, J=8.5Hz, 1H), 6.86-6.72 (m, 2H), 5.53 (s, 1H), 5.37 (s, 1H), 3.96-3.81 (m,1H), 3.73 (d, J=14.4 Hz, 1H), 2.93 (s, 1H), 2.83 (p, J=7.0, 6.3 Hz, 2H),2.40 (t, J=7.1 Hz, 2H), 1.67 (s, 2H), 1.61 (d, J=14.5 Hz, 4H), 1.43 (s,2H), 1.28-1.19 (m, 2H), 1.22-1.12 (m, 4H), 1.12 (s, 1H), 1.10 (s, 1H),1.05 (d, J=6.6 Hz, 2H), 0.87 (s, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.29 (s, 1H), 7.26 (s, 1H), 7.23 (d,J=7.9 Hz, 2H), 6.99 (d, J=8.0 Hz, 4H), 5.27 (s, 4H), 3.86 (d, J=13.5 Hz,2H), 3.74 (d, J=13.4 Hz, 2H), 2.69 (d, J=6.3 Hz, 2H), 2.57 (s, 6H), 1.35(dd, J=12.9, 6.3 Hz, 1H), 1.28 (s, 3H), 1.15 (s, 8H), 1.12 (s, 1H), 1.05(d, J=6.2 Hz, 6H), 0.83 (s, 6H).

1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=7.3 Hz, 1H), 7.11 (t, J=7.9 Hz,1H), 6.84-6.75 (m, 2H), 3.83 (dd, J=6.8, 2.8 Hz, 2H), 3.73 (d, J=13.4Hz, 1H), 3.60 (d, J=13.4 Hz, 1H), 1.63 (d, J=10.9 Hz, 5H), 1.56 (d,J=13.0 Hz, 1H), 1.29 (s, 6H), 1.15 (t, J=11.2 Hz, 2H), 1.08 (s, 2H),0.99 (d, J=6.2 Hz, 3H), 0.87-0.77 (m, 2H), 0.61 (q, J=5.6 Hz, 2H), 0.37(d, J=5.0 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.15 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.5 Hz,1H), 6.84-6.73 (m, 2H), 4.81 (s, 1H), 3.64 (s, 1H), 3.54 (s, 1H), 2.54(s, 0H), 1.91 (s, 2H), 1.82 (d, J=15.6 Hz, 5H), 1.64 (s, 8H), 1.25 (s,5H), 1.15 (s, 2H), 0.97 (d, J=6.1 Hz, 3H), 0.81 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=7.3 Hz, 1H), 7.13 (t, J=7.5 Hz,1H), 6.84 (d, J=7.6 Hz, 2H), 6.06 (td, J=11.1, 5.2 Hz, 1H), 5.46-5.37(m, 1H), 5.26 (d, J=10.4 Hz, 1H), 4.55 (d, J=4.8 Hz, 2H), 3.75 (d,J=13.6 Hz, 1H), 3.61 (d, J=13.6 Hz, 1H), 1.62 (d, J=10.9 Hz, 5H), 1.54(s, 1H), 1.31-1.12 (m, 8H), 0.98 (d, J=6.1 Hz, 3H), 0.81 (dd, J=22.0,11.4 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=7.3 Hz, 1H), 7.13 (t, J=7.8 Hz,1H), 6.84 (dd, J=11.9, 7.7 Hz, 2H), 4.65 (s, 2H), 3.75 (d, J=13.2 Hz,1H), 3.63 (d, J=13.3 Hz, 1H), 3.51 (s, 2H), 3.40 (t, J=7.0 Hz, 2H), 2.61(s, 1H), 2.54 (s, 1H), 2.02-1.94 (m, 2H), 1.86 (q, J=6.7 Hz, 2H), 1.63(s, 6H), 1.32 (s, 2H), 1.16 (s, 5H), 1.06 (d, J=6.6 Hz, 0H), 0.98 (d,J=6.1 Hz, 3H), 0.83 (d, J=11.3 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=7.4 Hz, 1H), 7.24 (t, J=7.6 Hz,1H), 7.13 (dt, J=16.6, 7.7 Hz, 2H), 6.94 (s, 0H), 3.77 (d, J=13.5 Hz,1H), 3.67 (d, J=13.5 Hz, 1H), 2.66 (q, J=6.4 Hz, 1H), 1.64 (s, 5H), 1.33(s, 1H), 1.25-1.18 (m, 1H), 1.16 (s, 1H), 1.05 (dd, J=30.4, 6.4 Hz, 3H),0.84 (t, J=11.6 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.23(d, J=7.4 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.86(t, J=7.4 Hz, 1H), 5.24 (s, 2H), 3.78 (d, J=13.6 Hz, 1H), 3.65 (d,J=13.4 Hz, 1H), 2.62 (d, J=6.4 Hz, 1H), 1.60 (d, J=10.3 Hz, 6H), 1.53(s, 1H), 1.27 (d, J=8.0 Hz, 2H), 1.12 (s, 4H), 1.04 (t, J=6.5 Hz, 1H),0.97 (d, J=6.1 Hz, 3H), 0.79 (t, J=12.4 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.18 (d, J=7.2 Hz, 1H), 7.15-7.07 (m, 1H),6.81 (d, J=7.7 Hz, 2H), 4.04 (q, J=7.0 Hz, 2H), 3.71 (d, J=13.5 Hz, 1H),3.58 (d, J=13.5 Hz, 1H), 2.64-2.52 (m, 1H), 1.63 (d, J=10.8 Hz, 5H),1.56 (d, J=13.5 Hz, 1H), 1.43 (t, J=6.9 Hz, 3H), 1.28 (d, J=6.5 Hz, 2H),1.28-1.17 (m, 1H), 1.17-1.02 (m, 2H), 0.98 (d, J=6.1 Hz, 3H), 0.84 (d,J=12.2 Hz, 1H), 0.78 (d, J=11.9 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.20-7.09 (m, 2H), 6.88-6.78 (m, 2H), 4.09(q, J=3.8 Hz, 2H), 3.77-3.67 (m, 1H), 3.71 (s, 2H), 3.58 (d, J=13.5 Hz,1H), 3.00 (s, 12H), 2.61-2.52 (m, 1H), 1.62 (d, J=11.5 Hz, 4H), 1.54 (d,J=13.4 Hz, 1H), 1.29 (s, 2H), 1.30-1.22 (m, 0H), 0.97 (d, J=6.1 Hz, 3H),0.79 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=4.8 Hz, 1H), 7.75 (t, J=7.6 Hz,1H), 7.50 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.1 Hz, 2H), 7.14 (t, J=7.8 Hz,1H), 6.94-6.82 (m, 2H), 5.17 (s, 2H), 3.84 (d, J=13.5 Hz, 1H), 3.70 (d,J=13.5 Hz, 1H), 2.65 (q, J=6.3 Hz, 1H), 1.61 (s, 5H), 1.55 (s, 0H),1.34-1.26 (m, 2H), 1.13-0.97 (m, 7H), 0.85-0.74 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.50 (d, J=4.5 Hz, 1H), 7.82(d, J=7.9 Hz, 1H), 7.38-7.30 (m, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.16 (d,J=8.1 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.88 (t, J=7.4 Hz, 1H), 5.14 (s,2H), 3.77 (d, J=13.4 Hz, 1H), 3.65 (d, J=13.3 Hz, 1H), 2.63 (d, J=7.0Hz, 1H), 1.61 (d, J=10.6 Hz, 5H), 1.26 (d, J=9.2 Hz, 2H), 1.12 (s, 4H),1.05 (d, J=5.5 Hz, 1H), 0.97 (d, J=6.1 Hz, 3H), 0.79 (s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.20-7.09 (m, 2H), 6.87-6.78 (m, 2H), 4.19(q, J=6.0 Hz, 1H), 3.93 (t, J=5.7 Hz, 2H), 3.88-3.81 (m, 1H), 3.78-3.69(m, 2H), 3.57 (d, J=13.5 Hz, 1H), 2.57 (dt, J=10.4, 5.3 Hz, 1H), 2.05(d, J=8.4 Hz, 1H), 1.93 (dd, J=14.2, 7.1 Hz, 2H), 1.83 (ddt, J=26.4,14.0, 6.6 Hz, 1H), 1.61 (d, J=12.3 Hz, 4H), 1.52 (d, J=13.3 Hz, 1H),1.31-1.23 (m, 2H), 1.14 (s, 3H), 1.01 (dd, J=29.9, 6.3 Hz, 3H), 0.80(dt, J=23.0, 11.0 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.21-7.10 (m, 2H), 6.87-6.80 (m, 2H), 4.79(t, J=5.2 Hz, 1H), 3.93 (t, J=5.7 Hz, 2H), 3.78-3.66 (m, 3H), 3.60 (q,J=10.4, 9.1 Hz, 3H), 2.59 (s, 1H), 1.61 (d, J=12.4 Hz, 4H), 1.51 (d,J=13.1 Hz, 1H), 1.26 (d, J=24.1 Hz, 4H), 1.20 (d, J=7.2 Hz, 4H), 1.14(s, 2H), 1.05 (s, 1H), 0.98 (d, J=6.1 Hz, 2H), 0.85-0.75 (m, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.8 Hz,1H), 7.02 (d, J=8.1 Hz, 1H), 6.88 (t, J=7.1 Hz, 1H), 5.21 (s, 2H), 3.71(dd, J=9.4, 5.6 Hz, 3H), 3.61 (d, J=13.9 Hz, 1H), 2.64 (s, 1H), 2.54 (s,1H), 1.63 (s, 5H), 1.33-1.25 (m, 1H), 1.21 (t, J=7.1 Hz, 2H), 0.99 (d,J=6.2 Hz, 3H), 0.81 (d, J=13.0 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.18 (d, J=7.4 Hz, 1H), 7.11 (d, J=7.8 Hz,1H), 6.87-6.77 (m, 2H), 4.03 (d, J=8.0 Hz, 2H), 3.72 (d, J=13.4 Hz, 1H),3.61-3.48 (m, 3H), 3.30 (s, 3H), 2.60 (s, 2H), 2.05-1.98 (m, 2H), 1.62(d, J=11.3 Hz, 5H), 1.54 (d, J=12.2 Hz, 1H), 1.27 (s, 3H), 1.14 (s, 4H),0.98 (d, J=6.0 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.14 (dd, J=17.4, 7.9 Hz, 2H), 6.83 (dd,J=12.1, 7.6 Hz, 2H), 4.08 (d, J=5.4 Hz, 2H), 3.77-3.70 (m, 3H),3.61-3.50 (m, 3H), 2.52 (d, J=16.8 Hz, 2H), 1.61 (d, J=12.1 Hz, 4H),1.52 (d, J=12.8 Hz, 1H), 1.29-1.16 (m, 3H), 1.15 (s, 1H), 0.97 (d, J=6.1Hz, 2H), 0.82 (d, J=11.9 Hz, 1H), 0.77 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.22-7.09 (m, 2H), 6.83 (t, J=7.7 Hz, 2H),4.12 (s, 2H), 3.72 (d, J=13.6 Hz, 1H), 3.59 (d, J=13.6 Hz, 1H), 2.89 (t,J=6.5 Hz, 2H), 2.63 (q, J=7.5 Hz, 3H), 2.54 (s, 1H), 1.63 (d, J=10.6 Hz,5H), 1.56 (d, J=13.2 Hz, 1H), 1.28 (t, J=7.4 Hz, 3H), 1.15 (s, 2H), 0.98(d, J=6.1 Hz, 3H), 0.81 (s, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 7.20 (t, J=7.7 Hz, 2H),6.94-6.81 (m, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.84 (d, J=13.1 Hz, 1H), 3.71(d, J=13.1 Hz, 1H), 2.76 (t, J=5.9 Hz, 2H), 2.68 (q, J=6.4 Hz, 1H), 2.35(s, 6H), 1.64 (s, 5H), 1.55 (d, J=12.7 Hz, 1H), 1.36 (dt, J=13.0, 6.7Hz, 1H), 1.16 (s, 6H), 1.05 (d, J=6.2 Hz, 3H), 0.86 (s, 1H), 0.81 (d,J=11.3 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=7.3 Hz, 1H), 7.15 (t, J=7.9 Hz,1H), 6.88 (t, J=9.1 Hz, 2H), 4.89-4.76 (m, 2H), 3.74 (d, J=13.6 Hz, 1H),3.63 (d, J=13.7 Hz, 1H), 3.00 (d, J=1.8 Hz, 3H), 2.84 (s, 3H), 2.80 (d,J=10.9 Hz, 0H), 2.55 (d, J=10.8 Hz, 2H), 1.92 (s, 1H), 1.57 (d, J=13.4Hz, 6H), 1.31 (s, 1H), 1.11 (s, 4H), 0.95 (d, J=6.1 Hz, 2H), 0.83-0.73(m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.22 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.8 Hz,1H), 6.90-6.78 (m, 2H), 4.11 (dt, J=7.3, 3.5 Hz, 1H), 3.70 (dd, J=13.7,7.0 Hz, 1H), 3.54 (t, J=13.3 Hz, 1H), 2.59 (s, 1H), 2.56 (d, J=12.6 Hz,1H), 2.00-1.89 (m, 1H), 1.76 (d, J=3.9 Hz, 1H), 1.70 (s, 4H), 1.57 (d,J=12.4 Hz, 7H), 1.48 (d, J=15.0 Hz, 1H), 1.28-1.20 (m, 4H), 1.15 (d,J=11.3 Hz, 1H), 1.10 (s, 1H), 1.05 (d, J=2.2 Hz, 3H), 0.99-0.92 (m, 5H),0.86 (s, 3H), 0.77 (t, J=13.6 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.90(t, J=7.4 Hz, 1H), 6.81 (dd, J=8.2, 5.4 Hz, 1H), 5.02 (q, J=6.7 Hz, 1H),3.73 (d, J=13.5 Hz, 1H), 3.67 (d, J=3.2 Hz, 5H), 2.65-2.52 (m, 2H), 1.68(s, 1H), 1.59 (d, J=11.1 Hz, 6H), 1.52 (dd, J=6.8, 4.6 Hz, 3H), 1.31 (s,2H), 1.12 (s, 5H), 1.09-1.01 (m, 0H), 0.97 (dd, J=6.2, 3.2 Hz, 3H), 0.82(s, 1H), 0.78 (d, J=12.0 Hz, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.18 (d, J=7.4 Hz, 1H), 6.94 (dd,J=12.7, 7.5 Hz, 2H), 3.89 (d, J=11.0 Hz, 1H), 3.74 (s, 2H), 3.63 (d,J=10.9 Hz, 1H), 2.81 (d, J=6.9 Hz, 1H), 1.41 (dd, J=12.7, 6.2 Hz, 1H),1.25-1.17 (m, 1H), 1.18 (s, 4H), 1.12 (d J=6.1 Hz, 2H), 0.89 (t, J=13.5Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.29-7.14 (m, 1H), 6.94-6.83 (m, 1H),4.01-3.91 (m, 1H), 3.89 (s, 1H), 3.67 (d, J=11.5 Hz, 0H), 2.78 (d, J=8.7Hz, 1H), 1.42-1.36 (m, 1H), 1.32 (d, J=13.6 Hz, 2H), 1.19 (s, 5H), 1.11(d, J=6.1 Hz, 2H), 0.88 (d, J=12.5 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.18 (s, 1H), 9.07 (s, 1H),7.56 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H),6.98 (t, J=7.5 Hz, 1H), 4.10 (dq, J=12.7, 6.1 Hz, 12H), 4.02 (s, 2H),3.58 (q, J=8.0 Hz, 1H), 3.20 (s, 2H), 2.72 (d, J=4.9 Hz, 3H), 2.25 (s,3H), 1.99 (s, 2H), 1.84 (s, 2H), 1.72 (s, 2H), 1.62 (t, J=14.2 Hz, 8H),1.55 (s, 4H), 1.52 (d, J=7.8 Hz, 1H), 1.31 (d, J=6.4 Hz, 3H), 1.14 (dd,J=23.8, 13.4 Hz, 3H), 0.94 (t, J=11.5 Hz, 1H), 0.80 (d, J=11.5 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.26-7.14 (m, 2H), 6.93 (d, J=8.1 Hz, 1H),6.86 (t, J=7.3 Hz, 1H), 3.99-3.88 (m, 1H), 3.83 (q, J=5.1, 4.4 Hz, 2H),3.73 (d, J=13.3 Hz, 1H), 3.59 (d, J=13.3 Hz, 1H), 3.33 (s, 1H), 2.57(dd, J=13.4, 7.2 Hz, 1H), 1.58 (d, J=11.9 Hz, 5H), 1.50 (d, J=12.6 Hz,1H), 1.27 (td, J=11.2, 10.3, 6.1 Hz, 2H), 1.16 (d, J=6.3 Hz, 3H), 1.11(s, 4H), 0.99 (dd, J=24.3, 6.3 Hz, 3H), 0.76 (q, J=12.8, 12.2 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=7.4 Hz, 1H), 7.16 (t, J=7.9 Hz,1H), 6.94-6.84 (m, 2H), 4.80 (s, 2H), 3.74 (d, J=13.9 Hz, 1H), 3.69 (s,3H), 3.64 (d, J=13.8 Hz, 1H), 2.62-2.51 (m, 1H), 1.77 (s, 1H), 1.61-1.49(m, 5H), 1.29 (s, 2H), 1.27 (dd, J=13.7, 7.7 Hz, 0H), 1.10 (s, 3H), 0.95(d, J=6.1 Hz, 3H), 0.79 (q, J=12.4, 11.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=7.4 Hz, 1H), 7.18 (t, J=7.8 Hz,1H), 6.94 (d, J=8.2 Hz, 1H), 6.87 (t, J=7.4 Hz, 1H), 4.04 (t, J=6.1 Hz,2H), 3.71 (d, J=13.6 Hz, 1H), 3.59 (d, J=13.6 Hz, 1H), 2.69-2.52 (m,3H), 2.07 (d, J=1.7 Hz, 2H), 2.00 (p, J=6.7 Hz, 2H), 1.58 (d, J=12.2 Hz,5H), 1.50 (d, J=12.7 Hz, 1H), 1.26 (dd, J=13.5, 7.8 Hz, 2H), 1.21-1.11(m, 2H), 1.05 (q, J=11.0, 6.1 Hz, 2H), 0.96 (dd, J=6.1, 1.7 Hz, 2H),0.79 (dt, J=22.8, 11.4 Hz, 2H).

Example 8: General Compound Syntheses 8

General procedure for preparation of target compounds 5:

Step A:

The solution of 2-hydroxybenzaldehyde 1 (5.0 mmol, 1.0 equiv), K₂CO₃(7.5 mmol, 1.5 equiv), compound 2 (5.0 mmol, 1.0 equiv) in CH₃CN (50 mL)was refluxed and monitored by TLC. After completion of the reaction, thesolution was cooled; solvent was evaporated under reduced pressure. Theresidue was poured into water (30 mL) and extracted with ethyl acetate(3×30 mL). The organic layer was washed with brine and dried overanhydrous MgSO₄. Filtration of MgSO₄ and evaporation of solvent undervacuum gave the crude product. The residue obtained was purified byusing HPLC to obtain the corresponding compound 3. Yield: 32-53%.

Step B:

Aldehyde 3 (0.55 mmol), amine 4 (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated anddissolved in 0.5 ml of DMSO, and purified using HPLC. Yield: 24-47%.

1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J=5.8 Hz, 1H), 7.26 (d, J=7.2 Hz,1H), 7.20 (t, J=7.8 Hz, 1H), 6.96-6.87 (m, 2H), 4.52 (s, 2H), 3.77 (d,J=12.9 Hz, 1H), 3.64 (d, J=12.9 Hz, 1H), 3.12 (p, J=7.0 Hz, 2H), 2.63(q, J=6.4 Hz, 1H), 1.82 (s, 1H), 1.61 (d, J=12.3 Hz, 5H), 1.54 (d,J=12.9 Hz, 1H), 1.33 (dd, J=11.6, 5.2 Hz, 2H), 1.14 (q, J=11.4, 9.5 Hz,3H), 1.09-0.96 (m, 6H), 0.81 (d, J=11.0 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=3.1 Hz, 1H), 7.79 (d, J=3.3 Hz,1H), 7.33 (d, J=7.5 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.10 (d, J=8.3 Hz,1H), 6.95 (t, J=7.3 Hz, 1H), 5.44 (d, J=2.5 Hz, 2H), 3.80 (d, J=13.8 Hz,1H), 3.68 (d, J=14.1 Hz, 1H), 2.61-2.52 (m, 2H), 1.67 (s, 1H), 1.55 (d,J=10.9 Hz, 5H), 1.47 (s, 0H), 1.26 (q, J=7.3 Hz, 2H), 1.07 (s, 5H), 0.96(d, J=6.1 Hz, 2H), 0.76 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=7.4 Hz, 1H), 7.21 (t, J=7.9 Hz,1H), 7.08 (d, J=8.2 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 6.46 (s, 1H), 5.24(d, J=2.9 Hz, 2H), 3.70 (d, J=14.0 Hz, 1H), 3.60 (d, J=13.9 Hz, 1H),2.53 (s, 1H), 2.24 (s, 3H), 1.58 (s, 6H), 1.29-1.21 (m, 2H), 1.12 (d,J=12.5 Hz, 2H), 1.04 (s, 2H), 0.93 (d, J=6.1 Hz, 3H) 0.81-0.71 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 2H), 7.27 (d, J=7.3 Hz, 2H), 7.20(t, J=7.9 Hz, 2H), 6.96-6.87 (m, 4H), 4.54 (s, 4H), 3.77 (d, J=12.9 Hz,2H), 3.64 (d, J=12.8 Hz, 2H), 3.05 (q, J=6.7 Hz, 4H), 2.63 (d, J=6.4 Hz,1H), 1.80 (s, 1H), 1.59 (s, 8H), 1.53 (s, 1H), 1.40 (d, J=7.3 Hz, 1H),1.40-1.29 (m, 7H), 1.14 (s, 4H), 1.12 (s, 1H), 0.99 (d, J=6.1 Hz, 6H),0.75 (t, J=7.4 Hz, 14H).

1H NMR (400 MHz, DMSO-d6) δ 7.19-7.08 (m, 2H), 6.82 (t, J=8.3 Hz, 2H),4.05 (s, 2H), 3.96 (s, 1H), 3.77-3.66 (m, 3H), 3.57 (d, J=13.8 Hz, 1H),1.68 (s, 7H), 1.61 (d, J=11.7 Hz, 3H), 1.52 (s, 3H), 1.29-1.16 (m, 2H),1.14 (s, 2H), 0.96 (d, J=6.1 Hz, 3H), 0.85-0.71 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.20-7.09 (m, 2H), 6.83 (dd, J=13.2, 7.4 Hz,2H), 4.12-4.05 (m, 2H), 3.80-3.70 (m, 3H), 3.57 (d, J=13.6 Hz, 1H), 3.34(d, J=6.7 Hz, 2H), 2.57 (dd, J=14.1, 7.7 Hz, 1H), 1.61 (d, J=11.8 Hz,4H), 1.52 (d, J=13.2 Hz, 1H), 1.29 (s, 1H), 1.30-1.16 (m, 1H), 1.14 (s,4H), 1.04 (d, J=6.6 Hz, 1H), 0.97 (d, J=6.1 Hz, 3H), 0.86-0.72 (m, 2H),0.49 (t, J=6.4 Hz, 2H), 0.20 (d, J=5.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J=7.5 Hz, 2H), 7.13 (d, J=8.1 Hz,1H), 6.86 (d, J=7.9 Hz, 4H), 4.12 (d, J=13.6 Hz, 4H), 3.99 (t, J=4.5 Hz,3H), 3.73 (d, J=13.6 Hz, 2H), 3.60 (d, J=13.7 Hz, 2H), 2.60 (d, J=5.7Hz, 1H), 2.54 (s, 1H), 1.62 (d, J=10.6 Hz, 9H), 1.53 (s, 1H), 1.29 (s,5H), 1.15 (s, 9H), 1.06 (s, 1H), 0.97 (d, J=6.1 Hz, 5H), 0.86-0.75 (m,4H).

1H NMR (400 MHz, DMSO-d6) δ 7.25 (t, J=8.9 Hz, 1H), 7.15 (s, 2H), 6.90(dd, J=16.3, 8.2 Hz, 3H), 4.86-4.71 (m, 2H), 4.19 (s, 1H), 3.73 (d,J=13.8 Hz, 1H), 3.62 (d, J=13.4 Hz, 2H), 3.18 (s, 1H), 2.84 (s, 2H),1.93 (s, 1H), 1.75 (d, J=12.6 Hz, 2H), 1.57 (s, 9H), 1.47 (s, 3H), 1.44(d, J=13.6 Hz, 1H), 1.30 (s, 5H), 1.10 (s, 6H), 1.03 (s, 1H), 0.95 (d,J=6.1 Hz, 3H), 0.77 (s, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=7.3 Hz, 1H), 7.18 (t, J=7.7 Hz,1H), 6.93 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.4 Hz, 1H), 4.25 (t, J=8.0 Hz,2H), 3.99 (t, J=6.2 Hz, 2H), 3.73 (d, J=13.7 Hz, 1H), 3.61 (d, J=13.8Hz, 1H), 3.55 (t, J=7.9 Hz, 2H), 2.61-2.50 (m, 1H), 1.96 (q, J=6.7 Hz,2H), 1.62-1.48 (m, 6H), 1.29 (s, 2H), 1.11 (td, J=22.0, 19.4, 8.9 Hz,4H), 0.96 (d, J=6.1 Hz, 3H), 0.78 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.20(t, J=7.8 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 6.79(d, J=1.7 Hz, 1H), 5.29 (s, 2H), 3.84 (s, 3H), 3.76 (d, J=13.8 Hz, 1H),3.63 (d, J=13.8 Hz, 1H), 2.59-2.47 (m, 1H), 1.56 (s, 5H), 1.23 (d, J=9.7Hz, 2H), 1.07 (s, 4H), 1.05-0.97 (m, 0H), 0.93 (d, J=6.1 Hz, 2H), 0.76(d, J=13.7 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.28-7.19 (m, 2H), 7.18 (d, J=8.0 Hz, 1H),7.01 (d, J=8.2 Hz, 1H), 6.89 (t, J=7.4 Hz, 1H), 6.60-6.50 (m, 3H), 4.31(d, J=2.4 Hz, 4H), 3.57 (d, J=13.9 Hz, 1H), 3.33 (s, 2H), 2.52 (d,J=17.3 Hz, 1H), 1.65 (s, 1H), 1.53 (s, 4H), 1.41 (d, J=13.1 Hz, 1H),1.23 (s, 2H), 1.11-1.04 (m, 1H), 1.04 (s, 1H), 0.90 (d, J=6.1 Hz, 3H),0.71 (dt, J=21.5, 11.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=2.0 Hz, 1H), 7.28 (d, J=7.3 Hz,1H), 7.21 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.4 Hz,1H), 6.81 (d, J=2.0 Hz, 1H), 5.42-5.30 (m, 2H), 3.78 (s, 3H), 3.65 (d,J=13.7 Hz, 1H), 3.55 (d, J=13.8 Hz, 1H), 2.74 (s, 1H), 2.53 (d, J=7.0Hz, 1H), 1.56 (d, J=9.1 Hz, 6H), 1.48 (d, J=13.3 Hz, 1H), 1.24 (s, 2H),1.23-1.11 (m, 1H), 1.09 (d, J=9.0 Hz, 1H), 0.89 (d, J=6.2 Hz, 3H),0.77_(s, 1H), 0.73 (d, J=11.7 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=7.3 Hz, 1H), 7.21 (t, J=7.9 Hz,1H), 7.10 (d, J=8.2 Hz, 1H), 6.97-6.87 (m, 2H), 5.15 (d, J=2.7 Hz, 2H),3.70 (d, J=13.8 Hz, 1H), 3.59 (d, J=14.0 Hz, 1H), 2.66 (q, J=7.6 Hz,2H), 2.54 (s, 1H), 1.66 (s, 1H), 1.57 (s, 5H), 1.48 (d, J=12.4 Hz, 1H),1.27 (s, 2H), 1.18 (t, J=7.5 Hz, 3H), 1.10 (s, 1H), 1.09-0.97 (m, 1H),0.92 (d, J=6.1 Hz, 3H), 0.75 (t, J=15.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.24-7.12 (m, 2H), 6.93 (d, J=8.0 Hz, 1H),6.85 (t, J=7.3 Hz, 1H), 4.81 (s, 1H), 4.46 (d, J=5.9 Hz, 2H), 4.40 (d,J=6.0 Hz, 2H), 4.13 (s, 2H), 3.73 (d, J=15.8 Hz, 4H), 3.60 (d, J=13.3Hz, 1H), 2.62 (s, 2H), 2.54 (s, 1H), 1.63 (s, 6H), 1.56 (d, J=12.5 Hz,1H), 1.29 (s, 3H), 1.16 (s, 5H), 1.06 (s, 1H), 0.98 (d, J=6.1 Hz, 3H),0.82 (s, 3H).

1H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J=10.2 Hz, 1H), 7.31-7.17 (m,2H), 6.96 (t, J=7.4 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 4.94 (d, J=5.8 Hz,1H), 4.56 (s, 2H), 3.94 (dd, J=13.1, 3.1 Hz, 1H), 3.82 (dd, J=12.9, 4.1Hz, 1H), 3.62 (s, 1H), 2.99 (d, J=2.3 Hz, 3H), 2.92 (d, J=2.1 Hz, 3H),2.80 (d, J=7.2 Hz, 1H), 1.69-1.61 (m, 4H), 1.58 (s, 1H), 1.44-1.35 (m,1H), 1.32 (d, J=6.8 Hz, 2H), 1.16 (s, 6H), 1.13 (dd, J=16.7, 8.8 Hz,3H), 1.09 (s 1H, 0.83 (t, J=12.5 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.29-7.17 (m, 2H), 6.94-6.79 (m, 6H),4.16 (dt, J=22.9, 6.0 Hz, 4H), 3.85 (d, J=13.1 Hz, 1H), 3.76 (s, 3H),3.70 (d, J=13.1 Hz, 1H), 2.66 (q, J=6.4 Hz, 1H), 2.28 (q, J=6.1 Hz, 2H),1.50 (d, J=12.9 Hz, 1H), 1.38-1.20 (m, 2H), 1.13 (s, 5H), 1.03 (d, J=6.2Hz, 3H), 0.81 (q, J=13.3, 12.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.21-7.10 (m, 2H), 6.90-6.79 (m, 2H), 4.10(p, J=5.6 Hz, 2H), 3.80 (t, J=4.8 Hz, 2H), 3.75 (d, J=13.9 Hz, 1H), 3.02(s, 8H), 2.56 (d, J=17.3 Hz, 1H), 1.62 (d, J=12.2 Hz, 5H), 1.51 (d,J=13.1 Hz, 1H), 1.27 (d, J=8.3 Hz, 3H), 1.23-0.95 (m, 6H), 0.80 (dd,J=21.9, 11.4 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.20-7.09 (m, 2H), 6.87 (d, J=8.2 Hz, 1H),6.80 (t, J=7.4 Hz, 1H), 4.10 (q, J=10.4, 6.9 Hz, 3H), 3.70 (d, J=13.4Hz, 1H), 3.56 (d, J=13.3 Hz, 1H), 2.64-2.52 (m, 1H), 1.89 (t, J=6.9 Hz,2H), 1.63 (d, J=10.5 Hz, 5H), 1.55 (s, 1H), 1.30 (s, 3H), 1.27 (d, J=6.4Hz, 0H), 1.20 (s, 6H), 1.15 (d, J=7.5 Hz, 1H), 0.97 (d, J=6.1 Hz, 3H),0.81 (t, J=15.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=7.5 Hz, 1H), 7.13 (t, J=7.7 Hz,1H), 6.82 (t, J=8.4 Hz, 2H), 4.01 (t, J=6.2 Hz, 2H), 3.71 (d, J=13.5 Hz,1H), 3.64 (s, 3H), 3.59 (d, J=13.4 Hz, 1H), 2.54 (s, 11H), 2.49 (s, 1H),2.11-2.03 (m, 2H), 1.63 (d, J=10.3 Hz, 5H), 1.56 (d, J=13.0 Hz, 1H),1.17 (d, J=13.8 Hz, 1H), 1.07 (d, J=6.8 Hz, 1H), 0.99 (d J=6.1 Hz, 3H),0.81 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.17 (s, 1H), 7.12 (s, 1H), 6.82 (d, J=8.2Hz, 2H), 3.98 (s, 2H), 3.72 (d, J=13.7 Hz, 1H), 3.58 (d, J=13.0 Hz, 1H),3.39 (s, 2H), 3.27 (s, 3H), 2.60 (s, 1H), 1.84 (s, 2H), 1.72 (s, 1H),1.63 (s, 7H), 1.28 (s, 3H), 1.15 (s, 4H), 1.06 (s, 1H), 0.98 (d, J=5.9Hz, 3H), 0.81 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=7.4 Hz, 1H), 7.21 (t, J=7.8 Hz,1H), 7.05 (d, J=8.2 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 5.49 (s, 2H),3.81-3.70 (m, 1H), 3.64 (d, J=14.0 Hz, 1H), 2.36 (s, 3H), 1.69 (s, 1H),1.58 (s, 5H), 1.52 (d, J=17.4 Hz, 1H), 1.29 (s, 2H), 1.26 (d, J=6.5 Hz,0H), 1.08 (dd, J=19.4, 9.7 Hz, 4H), 1.02 (t, J=5.9 Hz, 1H), 0.95 (d,J=6.1 Hz, 3H), 0.81 (d, J=12.6 Hz, 1H), 0.75 (d, J=11.9 Hz, 1H).

1H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.29-7.18 (m, 3H), 6.95(t, J=7.5 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.59 (s, 2H), 3.85 (d, J=11.9Hz, 1H), 3.70 (d, J=11.8 Hz, 1H), 2.80 (d, J=6.6 Hz, 1H), 2.64 (s, 1H),1.42 (dd, J=13.3, 6.7 Hz, 1H), 1.19 (s, 7H), 1.11 (d, J=6.2 Hz, 3H),0.88 (d, J=12.2 Hz, 3H), 0.74 (d, J=6.6 Hz, 2H), 0.43 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J=7.2 Hz, 1H), 7.12 (t, J=7.8 Hz,1H), 6.83 (d, J=7.7 Hz, 2H), 3.95-3.87 (m, 2H), 3.82 (dd, J=6.4, 2.8 Hz,2H), 3.72 (d, J=13.4 Hz, 1H), 3.58 (d, J=13.4 Hz, 1H), 3.36 (t, J=11.3Hz, 2H), 2.61 (d, J=6.2 Hz, 1H), 2.05 (s, 1H), 1.73 (d, J=13.2 Hz, 2H),1.63 (d, J=11.2 Hz, 5H), 1.54 (d, J=12.7 Hz, 1H), 1.44 (dt, J=12.5, 6.7Hz, 1H), 1.27 (s, 3H), 1.15 (t, J=10.9 Hz, 2H), 0.98 (d, J=6.2 Hz, 3H),0.81 (s, 2H).

1H NMR 400 MHz DMSO-d6) δ 7.26 (d, J=7.3 Hz, 2H), 7.16 (t, J=7.8 Hz,2H), 6.90 (s, 3H), 6.87 (d, J=7.5 Hz, 1H), 4.89 (d, J=11.3 Hz, 2H), 4.78(t, J=14.5 Hz, 2H), 4.19 (s, 0H), 4.10 (s, 1H), 3.79 (d, J=13.2 Hz, 3H),3.73 (d, J=13.7 Hz, 3H), 3.62 (d, J=13.6 Hz, 2H), 3.45 (d, J=10.9 Hz,1H), 3.14 (s, 8H), 2.81 (s, 1H), 2.69 (s, 1H), 2.55 (d, J=12.8 Hz, 1H),2.40 (s, 7H), 1.89 (s, 2H), 1.59 (s, 7H), 1.09 (d, J=6.2 Hz, 7H), 0.95(d, J=6.1 Hz, 5H), 0.77 (s, 5H).

1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.27 (d, J=7.4 Hz, 1H), 7.20(t, J=8.0 Hz, 1H), 6.95-6.84 (m, 2H), 4.77 (d, J=3.5 Hz, 2H), 3.98 (q,J=6.8 Hz, 1H), 3.74 (d, J=13.2 Hz, 1H), 3.62 (d, J=13.3 Hz, 1H), 2.63(s, 1H), 1.85 (dd, J=12.5, 6.2 Hz, 2H), 1.61-1.49 (m, 9H), 1.38 (s, 2H),1.30 (s, 2H), 1.12 (d, J=12.3 Hz, 1H), 1.08 (s, 4H), 0.98 (d, J=6.2 Hz,2H), 0.79 (d, J=16.2 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J=8.1 Hz, 3H), 6.96 (t, J=7.4Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 5.72 (s, 1H), 5.00 (s, 1H), 4.21 (s,2H), 4.20-4.15 (m, 1H), 3.87 (dd, J=13.3, 6.7 Hz, 1H), 3.80 (s, 2H),3.72 (dd, J=13.5, 8.4 Hz, 1H), 3.66 (s, 2H), 2.69 (q, J=6.4 Hz, 1H),1.36 (s, 1H), 1.25 (s, 3H), 1.16 (d, J=12.3 Hz, 5H), 1.06 (d, J=6.1 Hz,3H), 0.87-0.80 (m, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.24 (dd, J=30.2, 8.7 Hz, 2H), 6.96 (t,J=7.5 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 4.73 (d, J=3.5 Hz, 2H), 4.40 (d,J=13.2 Hz, 1H), 3.82 (d, J=11.8 Hz, 2H), 3.79-3.70 (m, 1H), 3.51 (s,2H), 2.84 (t, J=11.8 Hz, 1H), 2.71 (d, J=6.4 Hz, 1H), 2.38 (t, J=11.9Hz, 1H), 1.36 (dd, J=13.1, 6.6 Hz, 1H), 1.28 (s, 2H), 1.17 (dd, J=14.3,6.2 Hz, 9H), 1.06 (d, J=6.2 Hz, 3H), 0.84 (d, J=11.8 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.24 (dt, J=15.5, 5.9 Hz, 2H), 6.95(dd, J=8.0, 5.4 Hz, 2H), 5.18 (d, J=2.1 Hz, 2H), 3.86 (d, J=13.2 Hz,1H), 3.75 (d, J=13.2 Hz, 1H), 2.68 (q, J=6.4 Hz, 1H), 2.61 (s, 3H), 1.82(s, 1H), 1.55 (d, J=13.3 Hz, 1H), 1.37 (dt, J=12.8, 6.5 Hz, 1H), 1.30(s, 1H), 1.17-1.10 (m, 4H), 1.04 (d, J=6.2 Hz, 3H), 0.82 (s, 3H).

1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.30-7.23 (m, 1H), 7.21(d, J=7.4 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 5.11(s, 1H), 4.74 (s, 2H), 3.84 (d, J=11.9 Hz, 1H), 3.76 (d, J=11.8 Hz, 1H),2.86 (q, J=6.6 Hz, 1H), 1.49 (dt, J=13.5, 6.8 Hz, 1H), 1.26 (s, 1H),1.12 (p, J=7.1 Hz, 7H), 0.84 (d, J=11.7 Hz, 3H).

1H NMR (400 MHz, Chloroform-d) δ 7.27 (q, J=14.2, 11.0 Hz, 4H), 6.96 (t,J=7.4 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 4.65 (s, 2H), 4.00 (d, J=14.6 Hz,3H), 3.83 (d, J=12.0 Hz, 1H), 2.96 (s, 1H), 2.13 (s, 1H), 1.52 (s, 1H),1.30 (s, 2H), 1.19 (d, J=6.1 Hz, 4H), 0.94-0.83 (m, 2H).

Example 9: General Compound Syntheses 9

Step A:

A solution of 2-hydroxybenzaldehyde 1 (5.0 mmol, 1.0 equiv), K₂CO₃ (7.5mmol, 1.5 equiv), compound 2 (5.0 mmol, 1.0 equiv) in CH₃CN (50 mL) wasrefluxed and monitored by TLC. After completion of the reaction, thesolution was cooled; solvent was evaporated under reduced pressure. Theresidue was poured into water (30 mL) and extracted with ethyl acetate(3×30 mL). The organic layer was washed with brine and dried overanhydrous MgSO₄. Filtration of MgSO₄ and evaporation of solvent undervacuum gave the crude product. The residue obtained was purified byusing HPLC to obtain the corresponding compound 3. Yield: 29-53%.

Step B:

Aldehyde 3 (0.55 mmol), amine 4 (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified using HPLC. Yield: 31-48%.

1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=7.4 Hz, 1H), 7.23 (t, J=7.8 Hz,1H), 7.12 (d, J=8.1 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 5.40 (s, 2H), 3.70(d, J=13.8 Hz, 1H), 3.60 (d, J=14.0 Hz, 1H), 2.54 (s, 1H), 2.45 (d,J=1.9 Hz, 3H), 1.57 (s, 5H), 1.48 (s, 1H), 1.28-1.20 (m, 2H), 1.09 (s,3H), 0.92 (d, J=6.1 Hz, 3H), 0.75 (t, J=11.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=7.4 Hz, 1H), 7.20 (t, J=7.9 Hz,1H), 7.09 (d, J=8.3 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.09 (d, J=2.1 Hz,2H), 3.69 (d, J=13.9 Hz, 1H), 3.58 (d, J=13.9 Hz, 1H), 2.58-2.47 (m,2H), 2.23 (s, 3H), 2.02 (s, 3H), 1.57 (s, 5H), 1.49 (d, J=12.9 Hz, 1H),1.30-1.21 (m, 2H), 1.10 (t, J=11.3 Hz, 2H), 1.02 (q, J=6.7, 6.2 Hz, 1H),0.93 (d, J=6.1 Hz, 3H), 0.75 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J=7.2 Hz, 1H), 7.16 (t, J=7.7 Hz,1H), 7.12-7.06 (m, 1H), 6.96 (d, J=8.0 Hz, 3H), 6.87 (t, J=7.0 Hz, 2H),3.99 (q, J=7.4, 7.0 Hz, 4H), 3.73 (d, J=13.7 Hz, 1H), 3.61 (d, J=13.6Hz, 1H), 2.62-2.52 (m, 1H), 2.14-2.07 (m, 2H), 1.52 (q, J=16.7, 13.9 Hz,6H), 1.27 (t, J=8.1 Hz, 2H), 1.06 (t, J=12.0 Hz, 4H), 0.96 (d, J=6.1 Hz,3H), 0.75 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.34-7.28 (m, 1H), 7.25-7.17(m, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.94 (t, J=7.3 Hz, 1H), 5.31 (s, 2H),3.99 (s, 1H), 3.92 (s, 3H), 3.69 (d, J=13.7 Hz, 1H), 3.59 (d, J=14.1 Hz,1H), 1.58 (s, 7H), 1.26 (s, 2H), 1.19-0.97 (m, 3H), 0.92 (d, J=6.1 Hz,3H), 0.81-0.70 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.22 (d, J=7.3 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 6.90-6.80 (m, 2H), 4.11 (t, J=6.2 Hz, 2H), 3.75 (d, J=13.6 Hz, 1H),3.61 (d, J=13.5 Hz, 1H), 3.26 (t, J=7.7 Hz, 2H), 2.63 (q, J=6.3 Hz, 1H),2.50 (s, 2H), 2.24 (t, J=7.6 Hz, 2H), 1.65 (d, J=11.0 Hz, 4H), 1.59 (s,1H), 1.34-1.20 (m, 3H), 1.16 (s, 4H), 1.15-1.03 (m, 1H), 1.00 (d, J=6.1Hz, 3H), 0.88-0.77 (m, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.28-7.19 (m, 3H),7.02-6.90 (m, 2H), 5.26 (s, 2H), 4.11 (s, 3H), 3.86 (d, J=13.2 Hz, 1H),3.72 (d, J=13.4 Hz, 11H), 2.66 (d, J=7.1 Hz, 11H), 1.50 (d, J=12.9 Hz,11H), 1.32 (dd, J=13.0, 6.6 Hz, 1H), 1.17-1.07 (m, 3H), 1.03 (d, J=6.1Hz, 3H), 0.85-0.75 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.21-7.09 (m, 2H), 6.88-6.78 (m, 2H),4.13-4.06 (m, 2H), 3.80 (t, J=4.8 Hz, 2H), 3.73 (d, J=13.5 Hz, 1H), 3.63(t, J=4.8 Hz, 2H), 3.58 (d, J=13.3 Hz, 1H), 3.48 (t, J=4.8 Hz, 2H), 3.30(s, 3H), 2.56 (d, J=17.9 Hz, 1H), 1.62 (d, J=11.6 Hz, 4H), 1.53 (d,J=12.9 Hz, 1H), 1.28 (s, 11H), 1.15 (s, 5H), 1.01 (dd, J=30.7, 6.3 Hz,3H), 0.80 (q, J=10.3 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J=7.4 Hz, 1H), 7.22 (t, J=7.9 Hz,1H), 7.08 (d, J=8.2 Hz, 11H), 6.96 (d, J=6.5 Hz, 2H), 5.33 (s, 2H), 3.70(d, J=13.9 Hz, 1H), 3.61 (d, J=13.7 Hz, 1H), 2.55 (d, J=8.9 Hz, 1H),2.49 (s, 1H), 1.57 (s, 6H), 1.49 (s, 0H), 1.26 (s, 2H), 1.10 (s, 3H),1.09-0.98 (m, 1H), 0.93 (d, J=6.1 Hz, 3H), 0.81-0.71 (m, 2H).

1H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 7.29 (d, J=7.8 Hz, 0H),7.16 (d, J=6.9 Hz, 1H), 7.01-6.92 (m, 2H), 6.84 (d, J=8.2 Hz, 2H), 6.70(d, J=8.1 Hz, 2H), 4.73 (d, J=4.3 Hz, 2H), 4.42 (dd, J=15.1, 5.8 Hz,1H), 4.32 (dd, J=14.9, 5.3 Hz, 1H), 3.78 (d, J=15.2 Hz, 5H), 3.60 (d,J=11.6 Hz, 1H), 2.68-2.60 (m, 1H), 1.55 (t, J=14.7 Hz, 2H), 1.13 (d,J=11.1 Hz, 7H), 0.95 (d, J=6.3 Hz, 3H), 0.80 (d, J=13.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=7.5 Hz, 1H), 7.12 (d, J=8.0 Hz,1H), 6.88-6.78 (m, 2H), 4.06 (t, J=6.1 Hz, 2H), 3.92 (q, J=9.2 Hz, 2H),3.80 (t, J=6.2 Hz, 2H), 3.72 (d, J=13.7 Hz, 1H), 3.59 (d, J=13.1 Hz,1H), 2.61 (s, 1H), 2.08 (t, J=6.3 Hz, 2H), 1.63 (d, J=10.5 Hz, 5H), 1.54(s, 1H), 1.28 (s, 3H), 1.20 (d, J=12.1 Hz, 0H), 1.15 (s, 3H), 1.06 (s,1H), 0.98 (d, J=6.1 Hz, 2H), 0.82 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J=9.7 Hz, 1H), 4.14 (s, 1H), 4.04(d, J=8.8 Hz, 0H), 3.99 (s, 1H), 2.54 (s, 1H), 1.63 (s, 2H), 1.15 (s,2H), 0.98 (d, J=5.7 Hz, 1H), 0.80 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=7.4 Hz, 1H), 7.22 (t, J=7.4 Hz,1H), 7.09 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 4.92 (s, 2H), 3.65(d, J=13.8 Hz, 1H), 3.56 (d, J=13.9 Hz, 1H), 2.55 (d, J=6.8 Hz, 1H),2.40 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H), 1.57 (s, 4H), 1.50 (d, J=13.8Hz, 3H), 1.22 (dd, J=14.2, 7.5 Hz, 2H), 1.11 (d, J=12.3 Hz, 3H),1.04-0.96 (m, 1H), 0.91 (d, J=6.1 Hz, 3H), 0.80-0.70 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.18-7.08 (m, 3H), 6.81 (dd, J=12.9, 7.4 Hz,3H), 4.03 (hept, J=4.9 Hz, 3H), 3.74 (d, J=13.7 Hz, 1H), 3.67 (t, J=5.0Hz, 3H), 3.56 (d, J=13.7 Hz, 2H), 2.55 (d, J=5.5 Hz, 1H), 1.60 (d,J=12.9 Hz, 7H), 1.47 (d, J=13.8 Hz, 3H), 1.28 (s, 2H), 1.25 (d, J=6.5Hz, 1H), 1.21 (s, 12H), 1.12 (d, J=11.3 Hz, 1H), 1.06-0.93 (m, 4H), 0.77(dd, J=28.9, 12.5 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.27 (d, J=7.4 Hz, 1H), 7.20(t, J=7.7 Hz, 1H), 6.91 (dt, J=17.1, 8.1 Hz, 2H), 4.78 (d, J=3.5 Hz,2H), 3.90 (d, J=8.7 Hz, 1H), 3.75 (d, J=13.2 Hz, 1H), 3.63 (d, J=13.3Hz, 1H), 3.30 (s, 1H), 2.64 (s, 1H), 2.54 (s, 0H), 1.58 (s, 6H), 1.34(d, J=7.2 Hz, 1H), 1.30 (s, 2H), 1.09 (p, J=14.1, 13.5 Hz, 8H), 0.98 (d,J=6.0 Hz, 3H), 0.81 (s, 1H), 0.76 (d, J=12.7 Hz, 1H).

1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.7 Hz,1H), 6.94-6.84 (m, 2H), 4.91-4.78 (m, 2H), 3.74 (d, J=13.8 Hz, 1H),3.66-3.53 (m, 5H), 3.46 (s, 4H), 2.60-2.52 (m, 1H), 1.90 (s, 1H), 1.59(s, 5H), 1.30 (s, 2H), 1.12 (s, 5H), 0.95 (d, J=6.0 Hz, 3H), 0.83-0.72(m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.82 (d, J=4.9 Hz, 2H), 7.43(t, J=5.0 Hz, 1H), 7.09 (t, J=8.5 Hz, 2H), 6.71 (t, J=7.2 Hz, 2H), 3.96(d, J=16.3 Hz, 1H), 3.82-3.69 (m, 2H), 3.64 (d, J=13.8 Hz, 1H), 2.78 (q,J=6.9 Hz, 1H), 1.50 (t, J=13.8 Hz, 3H), 1.38 (dd, J=13.5, 6.8 Hz, 1H),1.26 (d, J=12.1 Hz, 3H), 1.02 (s, 4H), 0.98 (d, J=6.6 Hz, 3H), 0.68 (d,J=10.9 Hz, 1H), 0.57 (d, J=12.3 Hz, 1H).

1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J=11.7 Hz, 3H), 7.02 (d, J=8.2Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5.36 (s, 2H), 4.37 (s, 3H), 3.87 (d,J=13.2 Hz, 1H), 3.75 (d, J=13.3 Hz, 1H), 2.68 (d, J=7.1 Hz, 1H), 1.54(d, J=13.0 Hz, 1H), 1.36 (dd, J=12.9, 6.6 Hz, 1H), 1.28 (s, 1H), 1.13(s, 5H), 1.04 (d, J=6.1 Hz, 3H), 0.82 (s, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J=7.4 Hz, 1H), 7.22 (t, J=7.7 Hz,1H), 7.06 (d, J=8.3 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 5.49 (d, J=2.5 Hz,2H), 3.75 (d, J=13.8 Hz, 1H), 3.64 (d, J=13.8 Hz, 1H), 3.09 (p, J=7.0Hz, 1H), 2.60-2.52 (m, 1H), 1.57 (s, 4H), 1.26 (d, J=7.0 Hz, 7H), 1.09(s, 3H), 1.01 (s, 1H), 0.95 (d, J=6.1 Hz, 3H), 0.76 (t, J=12.8 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=7.4 Hz, 1H), 7.22 (t, J=7.8 Hz,1H), 7.06 (d, J=8.2 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 5.49 (s, 2H), 3.75(d, J=13.8 Hz, 1H), 3.64 (d, J=13.9 Hz, 1H), 2.74 (q, J=7.6 Hz, 2H),2.59-2.52 (m, 1H), 1.70 (s, 1H), 1.57 (s, 5H), 1.51 (d, J=15.5 Hz, 1H),1.28 (s, 2H), 1.23 (t, J=7.6 Hz, 3H), 1.07 (dt, J=17.1, 8.6 Hz, 2H),0.94 (d, J=6.1 Hz, 3H), 0.78 (q, J=11.6 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.27 (d, J=7.3 Hz, 1H), 7.20(t, J=7.9 Hz, 1H), 6.95-6.85 (m, 2H), 4.76 (d, J=3.3 Hz, 2H), 3.74 (d,J=13.1 Hz, 1H), 3.62 (d, J=13.2 Hz, 1H), 2.62 (d, J=6.8 Hz, 1H), 2.33(s, 1H), 1.58 (s, 4H), 1.51 (s, 1H), 1.28 (s, 9H), 1.22-0.95 (m, 6H),0.77 (s, 2H).

Example 10: General Compound Syntheses 10

Amine 1 (0.5 mmol) and compound 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified using HPLC. Yield: 23-58%.

The following compounds were synthesized according to the Scheme shownin Example 10 above:

1H NMR (400 MHz, DMSO-d6) δ 7.28 (dd, J=14.3, 7.3 Hz, 4H), 7.17 (t,J=7.1 Hz, 1H), 3.78 (dd, J=13.4, 3.2 Hz, 1H), 3.65 (d, J=13.1 Hz, 1H),2.43 (p, J=5.9 Hz, 1H), 1.71 (q, J=14.0, 13.6 Hz, 5H), 1.38-1.22 (m,1H), 1.29 (s, 1H), 1.26-1.17 (m, 1H), 1.17 (s, 1H), 1.04 (d, J=14.0 Hz,1H), 0.98 (d, J=6.6 Hz, 3H).

1H NMR (400 MHz, DMSO-d6) δ 7.36-7.26 (m, 4H), 7.21 (td, J=6.5, 6.0, 2.5Hz, 1H), 3.67 (s, 2H), 2.49 (s, 1H), 2.46-2.36 (m, 1H), 1.98 (pd, J=7.6,4.1 Hz, 2H), 1.91-1.79 (m, 1H), 1.82-1.72 (m, 1H), 1.69-1.56 (m, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.37-7.26 (m, 4H), 7.22 (d, J=6.8 Hz, 1H),3.68 (s, 2H), 2.29 (d, J=6.7 Hz, 2H), 1.93 (s, 1H), 1.68 (dp, J=13.3,6.7 Hz, 1H), 0.87 (d, J=6.6 Hz, 5H).

1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 2H), 7.46 (d, J=7.8 Hz, 2H), 7.23(d, J=7.6 Hz, 2H), 4.08 (s, 2H), 4.08 (d, J=12.1 Hz, 0H), 2.90 (s, 1H),2.32 (s, 3H), 2.14-2.06 (m, 2H), 1.76 (d, J=12.8 Hz, 2H), 1.59 (d,J=12.0 Hz, 1H), 1.40 (s, 1H), 1.36 (d, J=10.8 Hz, 1H), 1.22 (d, J=12.5Hz, 1H), 1.12 (dd, J=28.3, 13.2 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.29 (dt, J=15.0, 7.5 Hz, 6H), 7.19 (t,J=7.1 Hz, 2H), 3.16 (s, 4H), 2.70-2.64 (m, 2H), 2.55 (s, 1H), 1.60 (dd,J=13.2, 5.4 Hz, 3H), 1.49 (s, 4H), 1.47 (t, J=4.3 Hz, 1H), 1.45-1.32 (m,5H), 0.91 (d, J=6.6 Hz, 4H).

1H NMR (400 MHz, DMSO-d6) δ 7.31-7.20 (m, 3H), 7.16 (t, J=7.0 Hz, 1H),3.70 (s, 1H), 1.44 (q, J=7.0 Hz, 1H), 1.28 (s, 9H), 0.90 (t, J=6.6 Hz2H), 0.82 (s, 1H).

1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H), 7.69-7.62 (m, 1H), 7.47-7.41(m, 1H), 7.42 (s, 2H), 6.99 (s, 2H), 4.55 (s, 2H), 4.24 (t, J=5.9 Hz,2H), 3.00 (s, 2H), 1.65 (d, J=11.9 Hz, 5H), 1.55 (q, J=7.3 Hz, 3H), 1.30(s, 1H), 1.16 (p, J=12.0 Hz, 3H), 0.89 (q, J=11.8 Hz, 2H). Yield: 39%.

1H NMR (400 MHz, Chloroform-d) δ 7.24-7.12 (m, 2H), 6.87 (t, J=7.4 Hz,1H), 6.69 (d, J=8.1 Hz, 1H), 4.66 (p, J=7.2 Hz, 1H), 3.83 (d, J=13.0 Hz,1H), 3.70 (d, J=13.0 Hz, 1H), 2.69 (h, J=6.4 Hz, 1H), 2.47 (dtt, J=12.3,6.7, 2.7 Hz, 2H), 2.19 (d, J=10.1 Hz, 1H), 2.14 (d, J=10.2 Hz, 1H), 1.87(q, J=10.0 Hz, 2H), 1.79-1.61 (m, 5H), 1.60 (s, 1H), 1.42-1.22 (m, 2H),1.19 (s, 3H), 1.18-1.08 (m, 2H), 1.05 (d, J=6.2 Hz, 3H), 0.86 (s, 1H),0.81 (dd, J=12.1, 4.0 Hz, 1H). Yield: 32%.

1H NMR (400 MHz, DMSO-d6) δ 7.26-7.12 (m, 3H), 7.00-6.81 (m, 3H), 3.97(q, J=7.8 Hz, 1H), 3.82 (q, J=8.6 Hz, 1H), 3.70 (dt, J=14.5, 6.4 Hz,3H), 3.59 (d, J=11.8 Hz, 2H), 2.56 (p, J=6.0 Hz, 2H), 2.32 (s, 1H), 2.27(s, 1H), 2.25-2.17 (m, 2H), 1.89 (p, J=7.4 Hz, 1H), 1.73 (t, J=12.1 Hz,1H), 1.57 (d, J=11.6 Hz, 8H), 1.53-1.43 (m, 5H), 1.37 (d, J=9.9 Hz, 2H),1.28 (dt, J=17.8, 7.4 Hz, 5H), 1.17 (s, 2H), 1.11 (t, J=11.6 Hz, 5H),1.04 (d, J=7.9 Hz, 2H), 0.95 (d, J=5.7 Hz, 4H), 0.80 (d, J=10.1 Hz, 2H),0.75 (s, 2H). Yield 29%.

1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 6.96 (d, J=8.2 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 4.43-4.34 (m, 1H),3.69 (d, J=13.4 Hz, 1H), 3.58 (d, J=13.4 Hz, 1H), 2.58 (q, J=6.3 Hz,1H), 1.87 (d, J=11.8 Hz, 2H), 1.69 (s, 2H), 1.58 (d, J=10.5 Hz, 6H),1.50 (t, J=8.4 Hz, 4H), 1.35 (dt, J=20.6, 10.4 Hz, 4H), 1.30-1.21 (m,1H), 1.11 (td, J=22.2, 19.3, 9.7 Hz, 4H), 0.96 (d, J=6.1 Hz, 3H), 0.83(dd, J=18.2, 7.7 Hz, 1H), 0.75 (d, J=11.4 Hz, 1H). Yield 39%.

Example 11: General Compound Syntheses 11

Amine 1 (0.5 mmol), aldehyde 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified using HPLC. Yield: 31-54%.

The following compounds were synthesized according to the Scheme shownin Example 10 above:

1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.6 Hz,1H), 7.44 (t, J=7.5 Hz, 1H), 7.32 (t, J=8.1 Hz, 2H), 7.22 (t, J=7.8 Hz,1H), 7.05 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.13 (s, 2H), 3.75(d, J=13.7 Hz, 1H), 3.64 (d, J=13.7 Hz, 1H), 2.56 (q, J=6.2 Hz, 1H),1.58-1.44 (m, 6H), 1.28-1.17 (m, 2H), 1.04 (dt, J=28.1, 7.4 Hz, 5H),0.91 (d, J=6.1 Hz, 3H), 0.73 (t, J=12.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.66-7.59 (m, 1H), 7.56-7.49 (m, 1H),7.44-7.35 (m, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.07(d, J=8.1 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.17 (s, 2H), 3.75 (d, J=13.6Hz, 1H), 3.63 (d, J=13.8 Hz, 1H), 2.56 (s, 1H), 1.58 (d, J=12.3 Hz, 1H),1.57-1.43 (m, 5H), 1.27-1.17 (m, 2H), 1.08 (d, J=8.1 Hz, 2H), 1.03 (s,1H), 1.08-0.96 (m, 1H), 0.91 (d, J=6.1 Hz, 3H), 0.74 (t, J=12.1 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.44 (td, J=8.0, 5.9 Hz, 1H), 7.30 (d, J=6.8Hz, 3H), 7.26-7.11 (m, 2H), 7.02 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.4 Hz,1H), 5.15 (s, 2H), 3.77 (d, J=13.6 Hz, 1H), 3.66 (d, J=13.6 Hz, 1H),2.59 (q, J=6.3 Hz, 1H), 1.55 (d, J=12.9 Hz, 6H), 1.49 (s, 1H), 1.26 (dq,J=13.0, 6.8, 6.3 Hz, 2H), 1.05 (dt, J=21.5, 7.8 Hz, 5H), 0.95 (d, J=6.1Hz, 3H), 0.75 (dd, J=17.6, 7.0 Hz, 2H).

1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.2 Hz, 1H), 7.30 (d, J=7.4 Hz,1H), 7.27-7.16 (m, 4H), 7.10 (d, J=8.2 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H),5.09 (s, 2H), 3.73 (d, J=13.7 Hz, 1H), 3.63 (d, J=13.8 Hz, 1H), 2.56 (q,J=6.3 Hz, 1H), 2.34 (s, 3H), 1.59-1.44 (m, 6H), 1.21 (dd, J=14.0, 7.5Hz, 2H), 1.04 (dt, J=30.0, 7.8 Hz, 4H), 0.91 (d, J=6.1 Hz, 3H), 0.74 (t,J=12.1 Hz, 2H).

1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.32-7.19 (m, 3H), 7.04 (t, J=7.7 Hz,1H), 6.99-6.89 (m, 2H), 5.07 (s, 2H), 3.95 (d, J=13.1 Hz, 1H), 3.82 (d,J=13.1 Hz, 1H), 2.72 (q, J=6.4 Hz, 1H), 1.60 (d, J=9.5 Hz, 5H), 1.52 (d,J=13.1 Hz, 1H), 1.35 (dt, J=13.3, 6.6 Hz, 1H), 1.18-1.02 (m, 7H), 0.80(d, J=11.4 Hz, 2H).

Example 12: Individual Compound Syntheses

2-(1H-indol-7-yl)ethan-1-amine (0.5 mmol) and benzaldehyde (0.55 mmol)were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours, thenmixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C., 3 ml of methanol and 0.2 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated and dissolved in 0.5 ml of DMSO. The residue was purifiedusing HPLC. Yield: 47%. Brown gum. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s,1H), 7.37 (dd, J=6.7, 2.3 Hz, 1H), 7.29 (dd, J=9.1, 5.1 Hz, 5H),7.25-7.16 (m, 1H), 7.11 (s, 1H), 6.94-6.85 (m, 2H), 6.44-6.38 (m, 1H),3.74 (s, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H).

2-(1H-indol-4-yl)ethan-1-amine (0.5 mmol) and benzaldehyde (0.55 mmol)were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours, thenmixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C., 3 ml of methanol and 0.2 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated and dissolved in 0.5 ml of DMSO. The residue was purifiedusing HPLC. Yield: 56%. Yellow gum. 1H NMR (400 MHz, Chloroform-d) δ8.20 (s, 1H), 7.26 (s, 1H), 7.21 (s, 2H), 7.13 (t, J=7.7 Hz, 1H), 6.96(d, J=7.1 Hz, H), 6.61 (s, 1H), 3.83 (s, 2H), 3.15 (t, J=7.2 Hz, 2H),3.05 (t, J=7.2 Hz, 2H).

2-(cyclohex-1-en-1-yl)ethan-1-amine (0.5 mmol) and 3-methoxybenzaldehyde(0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2hours, then mixture was cooled, NaBH₄ (0.5 mmol) was added and stirredfor 4 hours. The mixture was heated for 2 hours at 60° C., 3 ml ofmethanol and 0.2 g of C-18 chromatographic phase were added, stirred for2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. Theresidue was purified using HPLC. Yield: 58%. Cream solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.70 (s, 2H), 7.29 (dd, J=15.7, 7.7 Hz, 2H), 7.11 (d,J=7.4 Hz, 1H), 6.90 (dd, J=8.4, 2.6 Hz, 1H), 5.47 (s, 1H), 3.82 (s, 3H),3.09 (s, 1H), 2.88 (t, J=8.2 Hz, 2H), 2.37 (t, J=8.4 Hz, 3H), 1.98 (s,2H), 1.91 (d, J=6.8 Hz, 2H), 1.67-1.57 (m, 2H), 1.60-1.50 (m, 2H).

To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at0° C. N-benzyl-2-(cyclohex-2-en-1-yl)acetamide (0.89 mmol) intetrahydrofuran (3 ml). The reaction mixture was then stirred at 60° C.for 3 hours, cooled to room temperature and quenched with 6N aqueoushydrochloric acid. The solvent was removed by distillation and water (10ml) 5 was added. The residue was purified using HPLC. Yield: 34%. 1H NMR(400 MHz, Chloroform-d) δ 7.37-7.19 (m, 3H), 5.66 (dq, J=9.8, 3.2 Hz,1H), 5.59-5.51 (m, 1H), 3.79 (s, 2H), 2.69 (ddt, J=11.2, 6.4, 3.3 Hz,2H), 2.14 (s, 1H), 1.96 (tp, J=5.1, 2.6 Hz, 2H), 1.82-1.66 (m, 2H),1.62-1.41 (m, 2H), 1.29-1.16 (m, 1H).

2-(cyclohex-1-en-1-ylmethyl)pyrrolidine (0.5 mmol), benzaldehyde (0.55mmol) were dissolved in 0.6 ml of CHCl₃; NaBHAc₃ (1.5 mmol) was addedand stirred for 4 hours. The mixture was heated for 12 hours at 60° C.,3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml ofDMSO. The residue was purified using HPLC. Yield: 32%. 1H NMR (400 MHz,DMSO-d6) δ 7.28 (q, J=5.5, 4.2 Hz, 4H), 7.21 (td, J=6.0, 3.0 Hz, 1H),5.42 (s, 1H), 4.00 (d, J=13.1 Hz, 1H), 3.16 (d, J=13.1 Hz, 1H), 2.75(dt, J=9.5, 4.8 Hz, 1H), 2.35-2.27 (m, 1H), 2.05 (q, J=8.6 Hz, 1H), 1.92(d, J=6.0 Hz, 4H), 1.83 (t, J=6.9 Hz, 1H), 1.80 (s, 1H), 1.54 (dddd,J=22.2, 16.9, 10.3, 5.1 Hz, 6H), 1.49-1.33 (m, 1H).

2-(cyclohex-1-en-1-ylmethyl)piperidine (0.5 mmol), benzaldehyde (0.55mmol) were dissolved in 0.6 ml of CHCl₃; NaBHAc₃ (1.5 mmol) was addedand stirred for 4 hours. The mixture was heated for 12 hours at 60° C.,3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml ofDMSO. The residue was purified using HPLC. Yield: 48%. 1H NMR (400 MHz,Chloroform-d) δ 7.34-7.21 (m, 4H), 7.21 (dd, J=7.6, 4.8 Hz, 1H), 5.16(d, J=8.9 Hz, 1H), 4.10 (d, J=13.4 Hz, 1H), 3.02 (d, J=13.4 Hz, 1H),2.88 (s, 1H), 2.82 (d, J=11.8 Hz, 1H), 2.27-2.14 (m, 2H), 2.11 (d, J=5.8Hz, 2H), 1.86 (td, J=11.8, 3.0 Hz, 1H), 1.72-1.64 (m, 1H), 1.53 (s, 1H),1.49-1.40 (m, 1H), 1.40-1.19 (m, 1H).

(R)-1-(cyclohex-1-en-1-yl)propan-2-amine (0.5 mmol) and benzaldehyde(0.55 mmol) were dissolved in 0.6 ml CHCl₃, NaBH(OAc)₃ (1.5 mmol) wasadded and stirred for 4 hours. The mixture was heated for 12 hours at60° C., 3 ml of methanol and 0.2 g of C-18 chromatographic phase wereadded, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 mlof DMSO. The residue was purified using HPLC. Yield: 47%. 1H NMR (400MHz, Chloroform-d) δ 7.37-7.24 (m, 3H), 7.22 (d, J=7.3 Hz, 2H), 5.47 (s,1H), 4.69 (ddt, J=10.7, 7.2, 3.4 Hz, 1H), 4.16 (ddq, J=14.8, 11.9, 7.3Hz, 3H), 4.00 (h, J=6.9 Hz, 1H), 3.44 (s, 1H), 3.28 (dd, J=13.3, 3.4 Hz,1H), 2.67 (dd, J=13.3, 9.8 Hz, 1H), 2.57 (q, J=7.3 Hz, 1H), 2.47 (dd,J=13.7, 7.0 Hz, 1H), 2.07-1.97 (m, 2H), 1.66-1.56 (m, 2H), 1.59-1.48 (m,3H), 1.32-1.05 (m, 5H).

(S)-1-(cyclohex-1-en-1-yl)propan-2-amine (0.5 mmol) and benzaldehyde(0.55 mmol) were dissolved in 0.6 ml CHCl₃, NaBH(OAc)₃ (1.5 mmol) wasadded and stirred for 4 hours. The mixture was heated for 12 hours at60° C., 3 ml of methanol and 0.2 g of C-18 chromatographic phase wereadded, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 mlof DMSO. The residue was purified using HPLC. Yield: 36%. 1H NMR (400MHz, Chloroform-d) δ 7.37-7.24 (m, 3H), 7.22 (d, J=7.3 Hz, 2H), 5.47 (s,1H), 4.69 (ddt, J=10.7, 7.2, 3.4 Hz, 1H), 4.16 (ddq, J=14.8, 11.9, 7.3Hz, 3H), 4.00 (h, J=6.9 Hz, 1H), 3.44 (s, 1H), 3.28 (dd, J=13.3, 3.4 Hz,1H), 2.67 (dd, J=13.3, 9.8 Hz, 1H), 2.57 (q, J=7.3 Hz, 1H), 2.47 (dd,J=13.7, 7.0 Hz, 1H), 2.07-1.97 (m, 2H), 1.66-1.56 (m, 2H), 1.59-1.48 (m,3H), 1.32-1.05 (m, 5H).

To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at0° C. N-(2-(bicyclo[4.1.0]heptan-1-yl)ethyl)benzamide (0.89 mmol) intetrahydrofuran (3 ml). The reaction mixture was then stirred at 60° C.for 3 hours, cooled to room temperature and quenched with 6N aqueoushydrochloric acid. The solvent was removed by distillation and water (10ml) was added. The residue was purified using HPLC. Yield: 37%. 1H NMR(400 MHz, DMSO-d6) δ 9.28 (s, 2H), 7.60-7.53 (m, 2H), 7.47-7.36 (m, 3H),4.11 (s, 2H), 2.94 (t, J=8.5 Hz, 2H), 1.83 (dq, J=13.3, 6.4 Hz, 1H),1.57 (dddd, J=34.1, 16.9, 13.1, 8.3 Hz, 5H), 1.20 (dd, J=14.8, 7.1 Hz,1H), 1.17-1.06 (m, 3H), 0.71 (q, J=7.3 Hz, 1H), 0.38 (dd, J=9.2, 4.2 Hz,1H), 0.20 (t, J=4.8 Hz, 1H).

To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at0° C. N-(2-(7,7-difluorobicyclo[4.1.0]heptan-1-yl)ethyl)benzamide (0.89mmol) in tetrahydrofuran (3 ml). The reaction mixture was then stirredat 60° C. for 3 hours, cooled to room temperature and quenched with 6Naqueous hydrochloric acid. The solvent was removed by distillation andwater (10 ml) was added. The residue was purified using HPLC. Yield:34%. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (dd, J=8.6, 5.1 Hz, 4H), 7.25-7.17(m, 1H), 3.68 (s, 2H), 2.57 (dd, J=15.3, 7.7 Hz, 2H), 2.00 (s, 1H),1.63-1.50 (m, 5H), 1.33 (dd, J=15.6, 8.4 Hz, 1H), 1.20 (dd, J=20.0, 9.1Hz, 4H).

2-benzyloctahydroisoquinolin-1(2H)-one (0.1 mmol) was dissolved inmethanol; an excess of hydrochloric acid (0.2 mmol) was added to thereaction mixture. The mixture was refluxed for 10 h, solvent wasremoved. The resulting compound was purified using HPLC. Yield: 44%. 1HNMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 7.54-7.48 (m, 2H), 7.47-7.38 (m,3H), 4.11 (t, J=8.7 Hz, 2H), 3.01-2.91 (m, 1H), 2.83 (s, 1H), 1.95 (dd,J=12.3, 8.9 Hz, 1H), 1.82 (d, J=12.6 Hz, 1H), 1.72 (d, J=12.8 Hz, 2H),1.66 (s, 2H), 1.56-1.46 (m, 1H), 1.45 (s, 1H), 1.32 (d, J=11.8 Hz, 1H),1.20 (d, J=10.4 Hz, 2H), 0.89 (d, J=12.2 Hz, 1H).

To a flask was added 2-(2-(benzylamino)ethyl)cyclohexane-1-carboxylicacid (1 mmol), anhydrous DMF 10 mL, potassium carbonate (2 mmol),catalytic amount of potassium iodide, stirring 10 min, then methyliodide (1 mmol) was added, reacted at 70° C., monitored by TLC. Afterthe reaction was allowed to cool to room temperature, the reactionsolution was poured into ice water, stirred for 30 min, extracted withethyl acetate. The organic layers were combined, washed with saturatedbrine. Dried over anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure, dried in vacuo. The crude residue waspurified by HPLC. Yield: 21%. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H),8.97 (s, 1H), 7.50 (s, 1H), 7.42 (s, 2H), 4.10 (s, 2H), 3.59 (d, J=5.1Hz, 2H), 2.94 (s, 1H), 2.80 (s, 1H), 2.07 (s, 1H), 1.76 (dd, J=26.2,12.2 Hz, 1H), 1.65 (s, 3H), 1.43 (s, 1H), 1.20 (s, 2H), 0.92 (d, J=11.6Hz, 1H).

To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at0° C. N-benzyl-2-(1-hydroxycyclohexyl)acetamide (0.89 mmol) intetrahydrofuran (3 ml). The reaction mixture was then stirred at 60° C.for 3 hours, cooled to room temperature and quenched with 6N aqueoushydrochloric acid. The solvent was removed by distillation and water (10ml) 5 was added. The residue was purified using HPLC. Yield: 22%. 1H NMR(400 MHz, Chloroform-d) δ 7.36-7.22 (m, 2H), 3.77 (s, 2H), 2.94-2.87 (m,2H), 1.69-1.58 (m, 3H), 1.35 (dt, J=22.6, 12.2 Hz, 3H), 1.26 (s, 1H).

To a solution of tert-butylbenzyl(2-(2-chloro-1-hydroxycyclohexyl)ethyl)carbamate (0.1 mmol) indichloromethane (25 mL) was slowly added trifluoroacetic acid (3.4 mmol)at 0° C. The reaction solution was stirred at room temperature for 5 h,and then 1N NaOH was added. The mixture was extracted withdichloromethane, and the organic layer was washed with brine, dried(Na₂SO₄), and filtered. The solvent was evaporated under reducedpressure to give the product. The crude residue was purified by HPLC.Yield: 46%. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 3H), 7.53-7.37 (m, 7H),5.07 (s, 1H), 4.19 (d, J=11.6 Hz, 3H), 4.08 (s, 1H), 4.01 (dd, J=7.1,3.6 Hz, 1H), 3.17 (s, 2H), 3.01 (d, J=9.0 Hz, 2H), 2.11 (t, J=9.8 Hz,1H), 1.96 (dd, J=14.8, 7.1 Hz, 1H), 1.87 (td, J=13.7, 13.2, 5.8 Hz, 1H),1.67 (q, J=14.9, 13.5 Hz, 2H), 1.59 (s, 4H), 1.36 (d, J=9.8 Hz, 3H).

2-(2-aminoethyl)cyclohexan-1-ol (0.5 mmol), benzaldehyde (0.55 mmol)were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours, thenmixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C., 3 ml of methanol and 0.2 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated and dissolved in 0.5 ml of DMSO. The residue was purifiedusing HPLC. Yield: 68%. 1H NMR (400 MHz, Chloroform-d) δ 7.34 (s, 1H),7.27 (d, J=6.7 Hz, 1H), 4.53 (s, 2H), 3.80 (s, 2H), 3.79 (s, 0H), 3.13(s, 1H), 3.01-2.89 (m, 1H), 2.63 (t, J=11.1 Hz, 1H), 2.00 (s, 1H), 1.42(dd, J=15.6, 9.5 Hz, 1H), 1.21 (q, J=11.8, 11.0 Hz, 4H), 1.07-0.97 (m,1H).

To a solution of tert-butylbenzyl(2-(2-methoxycyclohexyl)ethyl)carbamate (0.1 mmol) indichloromethane (25 mL) was slowly added trifluoroacetic acid (3.4 mmol)at 0° C. The reaction solution was stirred at room temperature for 5 h,and then 1N NaOH was added. The mixture was extracted withdichloromethane, and the organic layer was washed with brine, dried(Na₂SO₄), and filtered. The solvent was evaporated under reducedpressure to give the product. The crude residue was purified by HPLC.Yield: 57%. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 2H), 7.55 (d, J=7.9 Hz,2H), 7.41 (d, J=6.6 Hz, 2H), 4.10 (s, 2H), 3.20 (s, 2H), 2.88 (s, 2H),2.73 (td, J=9.9, 4.1 Hz, 1H), 2.05 (d, J=11.8 Hz, 1H), 1.97 (s, 1H),1.67 (d, J=12.0 Hz, 2H), 1.55 (d, J=11.2 Hz, 1H), 1.50-1.44 (m, 1H),1.27 (s, 1H), 1.13 (q, J=12.3 Hz, 2H), 1.01-0.89 (m, 2H).

Benzylamine (0.25 mmol) and 1-(adamantan-2-yl)ethan-1-one (0.3 mmol)were dissolved in 0.3 ml MeOH, heated at 100° C. for 2 hours, thenmixture was cooled, NaBH₄ (0.25 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C., 3 ml of methanol and 0.1 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated and dissolved in 0.25 ml of DMSO. The residue was purifiedusing HPLC. Yield: 34%. Cream solid. 1H NMR (400 MHz, DMSO-d6) δ 9.42(s, 1H), 8.54 (s, 1H), 7.68-7.58 (m, 2H), 7.43 (q, J=5.8 Hz, 3H), 4.20(q, J=8.6, 7.2 Hz, 1H), 4.13 (s, 1H), 3.22 (s, 1H), 2.49 (s, 1H), 2.06(s, 1H), 1.86-1.75 (m, 5H), 1.66 (d, J=11.0 Hz, 4H), 1.43 (s, 2H), 1.36(s, 2H), 1.28 (d, J=6.5 Hz, 2H).

To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at0° C. N-benzyl-2-(7-methoxynaphthalen-1-yl)acetamide (0.89 mmol) intetrahydrofuran (3 ml). The reaction mixture was then stirred at 60° C.for 3 hours, cooled to room temperature and quenched with 6N aqueoushydrochloric acid. The solvent was removed by distillation and water (10ml) 5 was added. The residue was purified using HPLC. Yield: 28%. 1H NMR(400 MHz, Chloroform-d) δ 7.76 (d, J=8.9 Hz, 1H), 7.66 (d, J=8.0 Hz,1H), 7.36-7.22 (m, 6H), 7.16 (dd, J=9.0, 2.5 Hz, 1H), 3.90 (s, 3H), 3.87(s, 1H), 3.85 (s, 2H), 3.27 (t, J=7.3 Hz, 2H), 3.07 (t, J=7.3 Hz, 2H).

2-(2-methoxynaphthalen-1-yl)ethan-1-amine (0.5 mmol) and benzaldehyde(0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2hours, then mixture was cooled, NaBH₄ (0.5 mmol) was added and stirredfor 4 hours. The mixture was heated for 2 hours at 60° C., 3 ml ofmethanol and 0.2 g of C-18 chromatographic phase were added, stirred for2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. Theresidue was purified using HPLC. Yield: 42%. 1H NMR (400 MHz, DMSO-d6) δ9.58 (s, 1H), 8.14 (d, J=8.7 Hz, 0H), 7.94-7.86 (m, 1H), 7.61 (d, J=7.0Hz, 1H), 7.45 (ddt, J=29.2, 22.6, 7.8 Hz, 3H), 4.22 (s, 1H), 3.51-3.43(m, 1H), 3.34 (s, 1H), 3.00 (s, 1H).

Benzylamine (0.5 mmol) and 1-(4-methoxynaphthalen-1-yl)propan-2-one(0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2hours, then mixture was cooled, NaBH₄ (0.5 mmol) was added and stirredfor 4 hours. The mixture was heated for 2 hours at 60° C., 3 ml ofmethanol and 0.2 g of C-18 chromatographic phase were added, stirred for2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. Theresidue was purified using HPLC. Yield: 36%. 1H NMR (400 MHz, DMSO-d6) δ8.19-8.13 (m, 1H), 7.95-7.88 (m, 1H), 7.47 (q, J=5.0 Hz, 2H), 7.32-7.19(m, 5H), 7.19 (s, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.94 (s, 3H), 3.84 (d,J=13.9 Hz, 1H), 3.73 (d, J=13.9 Hz, 1H), 3.26 (dd, J=13.6, 5.0 Hz, 1H),2.88 (s, 1H), 2.75 (dd, J=13.3, 8.1 Hz, 1H), 2.54 (s, 1H), 2.17 (s, 1H),0.95 (d, J=6.0 Hz, 3H).

To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at0° C. N-benzyl-2-(4-methylcyclohexyl)acetamide (0.89 mmol) intetrahydrofuran (3 ml). The reaction mixture was then stirred at 60° C.for 3 hours, cooled to room temperature and quenched with 6N aqueoushydrochloric acid. The solvent was removed by distillation and water (10ml) 5 was added. The residue was purified using HPLC. Yield: 31%. 1H NMR(400 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.60-7.54 (m, 1H), 7.42 (d, J=6.4 Hz,2H), 4.10 (s, 1H), 2.87 (t, J=8.2 Hz, 1H), 1.64 (d, J=8.1 Hz, 2H), 1.55(dt, J=11.6, 7.0 Hz, 1H), 0.86 (dd, J=15.6, 6.2 Hz, 3H).

2-(aminomethyl)benzenesulfonamide (0.5 mmol) and2-cyclohexylacetaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5 mmol)was added and stirred for 4 hours. The mixture was heated for 2 hours at60° C., 3 ml of methanol and 0.2 g of C-18 chromatographic phase wereadded, stirred for 2 hours, filtered, evaporated. The residue waspurified using HPLC. Yield: 34%. Light brown solid. 1H NMR (400 MHz,DMSO-d6) δ 7.86 (d, J=7.8 Hz, 1H), 7.54 (d, J=6.6 Hz, 2H), 7.45 (s, 1H),4.03 (s, 2H), 1.63 (d, J=12.2 Hz, 5H), 1.29 (t, J=7.2 Hz, 2H), 1.21-1.11(m, 1H), 0.84 (d, J=11.4 Hz, 2H).

(2-((methylsulfonyl)methyl)phenyl)methanamine (0.5 mmol) and2-cyclohexylacetaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5 mmol)was added and stirred for 4 hours. The mixture was heated for 2 hours at60° C., 3 ml of methanol and 0.2 g of C-18 chromatographic phase wereadded, stirred for 2 hours, filtered, evaporated. The residue waspurified using HPLC. Yield: 49%. Yellow gum. m/z: 309.22

To a solution of tert-butyl (2-cyclohexylethyl)(2-ureidobenzyl)carbamate(0.1 mmol) in dichloromethane (25 mL) was slowly added trifluoroaceticacid (3.4 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h, and then 1N NaOH was added. The mixture wasextracted with dichloromethane, and the organic layer was washed withbrine, dried (Na₂SO₄), and filtered. The solvent was evaporated underreduced pressure to give the product. The crude residue was purified byHPLC. Yield: 37%. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 2H), 8.88 (s,1H), 7.61 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.34 (t, J=7.7 Hz,1H), 7.12 (t, J=7.5 Hz, 1H), 6.12 (s, 5H), 4.12 (d, J=5.7 Hz, 2H), 2.99(s, 2H), 1.66 (s, 2H), 1.61 (d, J=16.2 Hz, 3H), 1.54 (q, J=7.5 Hz, 3H),1.30 (s, 1H), 1.17 (h, J=12.2 Hz, 3H), 0.88 (q, J=11.7 Hz, 2H).

Methyl 2-(2-(aminomethyl)phenyl)acetate (0.5 mmol) and2-cyclohexylacetaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours, then mixture was cooled, NaBH₄ (0.5 mmol)was added and stirred for 4 hours. The mixture was heated for 2 hours at60° C., 3 ml of methanol and 0.2 g of C-18 chromatographic phase wereadded, stirred for 2 hours, filtered, evaporated. The residue waspurified using HPLC. Yellow solid. Yield: 34%. 1H NMR (400 MHz, DMSO-d6)δ 7.27 (t, J=4.3 Hz, 1H), 7.27-7.16 (m, 3H), 4.46 (s, 2H), 3.42 (t,J=7.7 Hz, 2H), 3.33 (d, J=2.3 Hz, 1H), 1.65 (td, J=23.1, 18.8, 10.8 Hz,5H), 1.39 (q, J=7.3 Hz, 2H), 1.20 (d, J=10.4 Hz, 1H), 1.17-1.07 (m, 3H),0.92 (d, J=11.6 Hz, 1H), 0.86 (d, J=12.0 Hz, 1H).

1-cyclohexylpropan-2-amine (0.5 mmol) and2-((5-oxopyrrolidin-3-yl)methoxy)benzaldehyde (0.55 mmol) were dissolvedin 0.6 ml MeOH, heated at 100° C. for 2 hours, then mixture was cooled,NaBH₄ (0.5 mmol) was added and stirred for 4 hours. The mixture washeated for 2 hours at 60° C., 3 ml of methanol and 0.2 g of C-18chromatographic phase were added, stirred for 2 hours, filtered,evaporated and dissolved in 0.5 ml of DMSO. The residue was purifiedusing HPLC. Yield. 39%. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.27(d, J=7.4 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.88(t, J=7.4 Hz, 1H), 4.03-3.90 (m, 2H), 3.71 (d, J=13.7 Hz, 1H), 3.59 (d,J=13.7 Hz, 1H), 3.42 (t, J=8.9 Hz, 1H), 3.13 (dd, J=9.9, 5.7 Hz, 1H),2.90-2.80 (m, 1H), 2.62-2.52 (m, 1H), 2.33 (dd, J=16.6, 9.1 Hz, 1H),2.07 (dd, J=16.6, 6.8 Hz, 1H), 1.58 (d, J=11.5 Hz, 4H), 1.49 (d, J=13.3Hz, 1H), 1.27 (dt, J=13.5, 6.3 Hz, 2H), 1.20-1.00 (m, 4H), 0.96 (d,J=6.1 Hz, 3H), 0.77 (s, 2H).

Example 13: Individual Compound Syntheses 2 B156:N-benzyl-2-(cyclohex-3-enyl)ethanamine hydrochloride

Step 1: Preparation of 2

To a mixture of (methoxymethyl)triphenylphosphonium chloride (136.7 g,399.4 mmol, 2.2 eq) in THF (450 mL) was added potassium tert-butylate(40.7 g, 363 mmol, 2.0 eq) at 0° C. for 20 min. Then, 1 (20 g, 181.6 eq,1.0 eq) was added and the reaction mixture was stirred at roomtemperature. After completion, the mixture was poured into water,extracted with ethyl acetate and washed with brine. The combined organicphases were dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography to give the product 2(24.4 g) as an oil.

Step 2: Preparation of 3

To a mixture of 2 (12 g, 86.8 mmol, 1.0 eq) in THF (347 mL, c=0.25) wasadded aq. HCl (6N, 72 mL, 434 mmol, 5.0 eq). The reaction mixture wasstirred at room temperature for 1.5 h. After completion, water (100 mL)was added and the resulting mixture was extracted with EA (80 mL×3). Theorganic phases were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography to give the product 3 (2.6 g, yield=24.2%) as an oil.

Step 3: Preparation of 4

To a solution of 3 (200 mg, 1.6 mmol, 1.0 eq) in DCM (3.5 mL, c=0.46)was added benzylamine (173 mg, 1.6 mmol, 1.0 eq) and MgSO₄ (290 mg, 2.4mmol, 1.5 eq). After that, AcOH (0.4 mL) and NaBH₃CN (182 mg, 4.8 mmol,3.0 eq) were added and the reaction mixture was stirred at roomtemperature overnight. After completion, the mixture was poured intowater, extracted with ethyl acetate and washed with brine. The combinedorganic phases were dried over Na₂SO₄, filtered and concentrated invacuum. The residue was purified by column chromatography to give theproduct 4 (32 mg, yield=9.3%) as a solid.

Step 4: Preparation of B156

A mixture of 4 (26 mg, 0.12 mmol, 1.0 eq) in HCl/MeOH (1N, 2 mL, c=0.06)was stirred at room temperature for 1 h. After completion, thesuspension was filtered and concentrated under reduced pressure to givethe product B156 (31 mg, yield=100%) as a solid. ¹H NMR (400 MHz, D₂O):δ 7.43-7.41 (m, 5H), 5.68-5.63 (m, 2H), 4.16 (s, 2H), 3.06-3.02 (m, 2H),2.03-1.89 (m, 3H), 1.66-1.57 (m, 5H), 1.21-1.12 (m, 1H); Mass: m/z=216[M−HCl+H]⁺

B157: N-benzyl-1-(cyclohex-3-enyl)propan-2-amine

Step 1: Preparation of 2

To a mixture of 1 (1.0 g, 8.07 mmol, 1.0 eq) in THF (16 mL, c=0.5) wasadded dropwise CH₃MgBr (3N, 2.9 mL, 8.5 mmol, 1.05 eq) at −0° C. for 20min and the mixture was stirred at room temperature for 1 h. Aftercompletion, the resulting mixture was poured into water, extracted withethyl acetate and washed with brine. The combined organic phases weredried over Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by column chromatography to give the product 2 (200 mg,yield=17.7%) as an oil.

Step 2: Preparation of 3

To a mixture of 2 (100 mg, 0.7 mmol, 1.0 eq) in DCM (3.5 mL, c=0.2) wasadded PCC (231 mg, 1.1 mmol, 1.5 eq) and the reaction mixture wasstirred at room temperature overnight. After completion, the resultingmixture was filtered through celite and the filtrate was concentrated todryness to obtain the product 3 (100 mg, yield=100%).

Step 3: Preparation of B157

To a solution of 3 (200 mg, 1.44 mmol, 1.0 eq) in DCM (5 mL, c=0.3) wasadded benzylamine (150.2 mg, 1.44 mmol, 1.0 eq) and MgSO₄ (260 mg, 2.16mmol, 1.5 eq). Then AcOH (0.36 mL) and NaBH₃CN (164 mg, 4.32 mmol, 3.0eq) was added and the reaction mixture was stirred at room temperatureovernight. After completion, the mixture was poured into water,extracted with ethyl acetate and washed with brine. The combined organicphases were dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography to give the product B157(11 mg, yield=2.9%) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.34-7.19(m, 5H), 5.61 (s, 2H), 3.79-3.66 (m, 2H), 2.66-2.65 (m, 1H), 2.00-1.00(m, 12H); Mass: m/z=230 [M+H]⁺

B158: 6-((benzylamino)methyl)benzo[c][1,2]oxaborol-1 (3H)-ol

Step 1: Preparation of 2

To a mixture of 1 (2.0 g, 9.3 mmol, 1.0 eq) in DCM (46 mL, c=0.2) wasadded TEA (3.3 g, 32.5 mmol, 3.5 eq) at room temperature for 20 min.Then acetic anhydride (2.5 g, 24.2 mmol, 2.6 eq) was added dropwise atroom temperature for 10 min and the reaction mixture was stirred for 1h. After completion, the mixture was poured into water, extracted withethyl acetate and washed with brine. The combined organic phases weredried over Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by column chromatography to give the product 2 (1.92 g,yield=69%) as a solid.

Step 2: Preparation of 3

A solution of 2 (12 g, 40 mmol, 1.0 eq), bis(pinacolato)diboron (15.18g, 60 mmol, 1.5 eq) and potassium acetate in dioxane (160 mL, c=0.25)was added trans-dichlorobis(triphenyl-phosphine)palladium(II) (3.3 g, 4mmol, 0.1 eq) under nitrogen and the solution was heated at refluxovernight. After completion, the mixture was filtered and concentratedin vacuum. The crude was purified by column chromatography to give theproduct 3 (10.82 g, yield=77.7%) as a solid.

Step 3: Preparation of 4

To a solution of 3 (8 g, 23 mmol, 1.0 eq) in MeOH (24 mL) was addedsodium hydroxide (3.7 g, 92 mmol, 4.0 eq) in MeOH (18.4 mL) and thesolution was stirred at room temperature for 4 h. After that, thereaction mixture was concentrated in vacuum. The residue was dissolvedin THF again and aq.HCl (2N) was added dropwise below 15° C. withstirring and the pH of the mixture was adjusted to 1. After that, themixture was extracted with ethyl acetate and washed with brine. Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuum. The resulting crude was washed by 30% EA/PE toget the pure product 4 (2.8 g, yield=74.3%) as a solid.

Step 4: Preparation of 5

To a mixture of 4 (1.5 g, 9.14 mmol, 1.0 eq) in DCM (183 mL, c=0.05) wasadded PCC (3.95 g, 13.7 mmol, 1.5 eq) and the reaction solution wasstirred at room temperature for 1.5 h. After completion, the mixture wasfiltered and the filtrate was washed with aq.HCl (2N, 50 mL×2) andaq.NaOH (2N, 40 mL×2). After that, the pH of the aqueous phase wasadjusted to 1-2 by hydrochloric acid and extracted with ethyl acetate.The combined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuum. The resulting crude was washed by 5% EA/PE toget the pure product 5 (786 mg, yield=53%) as a solid.

Step 5: Preparation of 6

To a solution of 5 (50 mg, 0.309 mmol, 1.0 eq) and benzylamine (33.1 mg,0.309 mmol, 1.0 eq) in DCM (1.2 mL, c=0.25) was added sodium sulfate(87.8 mg, 0.618 mmol, 2.0 eq) and the reaction mixture was stirred atroom temperature under nitrogen overnight. After completion, thesuspension was filtered and the filtrate was concentrated under reducedpressure to give the crude 6 (93 mg, y=122%) as a solid.

Step 6: Preparation of B158

To a solution of 6 (40 mg, 0.16 mmol, 1.0 eq) in MeOH (1.6 mL, c=0.1)was added platinum(IV) oxide (3.6 mg, 0.016 mmol, 0.1 eq) and thereaction mixture was stirred at room temperature for 45 min under H₂.After completion, the suspension was filtered and the filtrate wasconcentrated under reduced pressure to give the product B158 (25 mg,y=62%) as a solid.

¹H NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 7.70-7.19 (m, 8H), 4.96 (s,2H), 4.10 (s, 1H), 3.71 (s, 2H), 3.17 (s, 2H); Mass: m/z=254[M+H]⁺

B159: 6-(2-(benzylamino)ethyl)benzo[c][1,2]oxaborol-1 (3H)-ol

Step 1: Preparation of 2

To a mixture of (Methoxymethyl)triphenylphosphonium chloride (15.5 g,45.1 mmol, 4.87 eq) in THF (60 mL) was added potassium tert-butylate(4.78 g, 42.6 mmol, 4.6 eq) at 0° C. for 20 min. Then, a mixture of 1(20 g, 181.6 eq, 1.0 eq) in THF (32.6 mL) was added and the reactionmixture was stirred at 0° C. After completion, the mixture was pouredinto water, extracted with ethyl acetate and washed with brine. Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography to give the product 2 (1.2 g, yield=68%) as a solid.

Step 2: Preparation of 3

To a mixture of 2 (1.2 g, 6.3 mmol, 1.0 eq) in THF (25 mL, c=0.25) wasadded aq.HCl (6N, 6.2 mL, 95 mmol, 15.0 eq) and the reaction mixture wasstirred at room temperature for 1.5 h. After completion, water (20 mL)was added and the resulting solution was extracted with EA (15 mL×3).The organic phases were washed with brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography to give the product 3 (420 mg, yield=38%) as asolid.

Step 3: Preparation of B159

To a solution of benzylamine acetate (142 mg, 0.85 mmol, 3.0 eq) in DMAc(1.9 mL, c=0.3) was added NaBH(OAc)₃ (121 mg, 0.57 mmol, 2.0 eq) andMgSO₄ (50.5 mg, 0.46 mmol, 1.5 eq) and the reaction mixture was stirredat room temperature for 0.5 h. Then, a mixture of 3 (50 mg, 0.28 mmol,1.0 eq) in DMAc (0.5 mL) was added and the resulting solution wasstirred at room temperature. After completion, the suspension wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by C-18 reverse phase HPLC to afford the productB159 (44 mg, yield=58%) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.05(brs, 1H), 8.22 (s, 1H), 7.55 (s, 1H), 7.36-7.25 (m, 8H), 4.94 (s, 2H),3.81 (s, 2H), 2.81 (s, 4H); Mass: m/z=268 [M+H]⁺

B162: N-benzyl-1-(3,4-dimethylcyclohex-3-en-1-yl)propan-2-amine

Step 1: Preparation of 3

To a solution of 1 (708 mg, 12.62 mmol, 1.28 eq) in cyclohexane (1.4 mL)2 was added (810 mg, 9.86 mmol, 1.0 eq) and the reaction mixture wasstirred at 60° C. overnight. After completion, the suspension wasconcentrated under reduced pressure to give the product 3 (540 mg,yield=39.7%) as an oil.

Step 2: Preparation of 4

To a solution of (methoxymethyl)triphenylphosphonium chloride (6.0 g,17.6 m mol, 4.87 eq) in THF (28 mL) was added potassium tert-butylate(1.86 g, 16.55 mmol, 4.6 eq) at 0° C. and the mixture was stirred for 20min. Then, 3 (500 mg, 3.6 eq, 1.0 eq) in THF (8 mL) was added and theresulting mixture was stirred at room temperature. After completion, themixture was poured into water, extracted with ethyl acetate and washedwith brine. The combined organic phases were dried over Na₂SO₄, filteredand concentrated in vacuum. The residue was purified by columnchromatography to give the product 4 (504 mg, yield=84.8%) as an oil.

Step 3: Preparation of 5

To a solution of 4 (1.0 g, 6.0 mmol, 1.0 eq) in THF (30 mL, c=0.2) wasadded aq.HCl (6N, 15 mL, 90 mmol, 15.0 eq) and the reaction mixture wasstirred at room temperature for 1.5 h. After completion, water (25 mL)was added and the mixture was extracted by EA (20 mL×3). The combinedorganic phases were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography to give the product 5 (897 mg, yield=98%) as an oil.

Step 4: Preparation of 6

To a solution of 5 (600 mg, 3.95 mmol, 1.0 eq) in THF (8 mL, c=0.5) wasadded dropwise CH₃MgBr (3N, 1.4 mL, 4.14 mmol, 1.05 eq) at 0° C. for 20min and then the mixture was stirred at room temperature for 1 h. Aftercompletion, the mixture was poured into water, extracted with ethylacetate and washed with brine. The combined organic phases were driedover Na₂SO₄, filtered and concentrated in vacuum to give the crudeproduct 6 (575.6 mg, yield=87.8%) as an oil.

Step 5: Preparation of 7

To a solution of 6 (550 mg, 3.57 mmol, 1.0 eq) in DCM (18 mL, c=0.2) wasadded PCC (1.15 g, 15.36 mmol, 1.5 eq) and the reaction mixture wasstirred at room temperature overnight. After completion, the resultingmixture was filtered through a pad of celite and the filtrate wasconcentrated to dryness. The residue was purified by columnchromatography to give the product 7 (150 mg, yield=27.6%) as an oil.

Step 6: Preparation of B162

To a solution of 7 (60 mg, 0.361 mmol, 1.0 eq) in MeOH (1.8 mL, c=0.2)was added benzylamine (155 mg, 1.444 mmol, 4.0 eq) and MgSO₄ (60 mg) andthe reaction mixture was stirred at 25° C. for 1 h. Then, AcOH (0.1 mL)and NaBH₃CN (68 mg, 1.083 mmol, 3.0 eq) was added and the reactionmixture was stirred at 80° C. overnight. After completion, thesuspension was concentrated in vacuum and the residue was purified bycolumn chromatography to give the desired product B162 (3.5 mg,yield=4%) as a yellow solid. ¹H NMR (400 MHz, DMSO): δ7.59-7.32 (m, 5H),4.13-4.05 (m, 2H), 2.82-2.73 (m, 1H), 1.75-1.20 (m, 18H). Mass: m/z=258[M+H]⁺

B385: N-(2-cyclobutoxybenzyl)-1-cyclohexylpropan-2-amine

(2-cyclobutoxyphenyl)methanamine (0.5 mmol) and 1-cyclohexylpropan-2-one(0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2hours; then the mixture was cooled, NaBH₄ (0.5 mmol) was added andstirred for 4 hours. The mixture was heated for 2 hours at 60° C.; 3 mlof methanol and 0.2 g of C-18 chromatographic phase were added, stirredfor 2 hours, filtered, evaporated. The residue was purified by HPLC.Yield: 39%.

1H NMR (400 MHz, Chloroform-d) δ 7.24-7.12 (m, 2H), 6.87 (t, J=7.4 Hz,1H), 6.69 (d, J=8.1 Hz, 1H), 4.66 (p, J=7.2 Hz, 1H), 3.83 (d, J=13.0 Hz,1H), 3.70 (d, J=13.0 Hz, 1H), 2.69 (h, J=6.4 Hz, 1H), 2.47 (dtt, J=12.3,6.7, 2.7 Hz, 2H), 2.19 (d, J=10.1 Hz, 1H), 2.14 (d, J=10.2 Hz, 1H), 1.87(q, J=10.0 Hz, 2H), 1.79-1.61 (m, 5H), 1.60 (s, 1H), 1.42-1.22 (m, 2H),1.19 (s, 3H), 1.18-1.08 (m, 2H), 1.05 (d, J=6.2 Hz, 3H), 0.86 (s, 1H),0.81 (dd, J=12.1, 4.0 Hz, 1H). m/z=302.3

B386:N-(2-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzyl)-1-cyclohexylpropan-2-amine

1-cyclohexylpropan-2-amine (0.5 mmol) and2-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzaldehyde (0.55 mmol) weredissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours; then themixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C.; 3 ml of methanol and 0.2 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated. The residue was purified by HPLC. Yield: 42%.

1H NMR (400 MHz, DMSO-d6) δ 7.26-7.12 (m, 3H), 7.00-6.81 (m, 3H), 3.97(q, J=7.8 Hz, 1H), 3.82 (q, J=8.6 Hz, 1H), 3.70 (dt, J=14.5, 6.4 Hz,3H), 3.59 (d, J=11.8 Hz, 2H), 2.56 (p, J=6.0 Hz, 2H), 2.32 (s, 1H), 2.27(s, 1H), 2.25-2.17 (m, 2H), 1.89 (p, J=7.4 Hz, 1H), 1.73 (t, J=12.1 Hz,1H), 1.57 (d, J=11.6 Hz, 8H), 1.53-1.43 (m, 5H), 1.37 (d, J=9.9 Hz, 2H),1.28 (dt, J=17.8, 7.4 Hz, 5H), 1.17 (s, 2H), 1.11 (t, J=11.6 Hz, 5H),1.04 (d, J=7.9 Hz, 2H), 0.95 (d, J=5.7 Hz, 4H), 0.80 (d, J=10.1 Hz, 2H),0.75 (s, 2H). m/z=356.2

B387: 1-cyclohexyl-N-(2-(cyclohexyloxy)benzyl)propan-2-amine

(2-(cyclohexyloxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 51%.

1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 6.96 (d, J=8.2 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 4.43-4.34 (m, 1H),3.69 (d, J=13.4 Hz, 1H), 3.58 (d, J=13.4 Hz, 1H), 2.58 (q, J=6.3 Hz,1H), 1.87 (d, J=11.8 Hz, 2H), 1.69 (s, 2H), 1.58 (d, J=10.5 Hz, 6H),1.50 (t, J=8.4 Hz, 4H), 1.35 (dt, J=20.6, 10.4 Hz, 4H), 1.30-1.21 (m,1H), 1.11 (td, J=22.2, 19.3, 9.7 Hz, 4H), 0.96 (d, J=6.1 Hz, 3H), 0.83(dd, J=18.2, 7.7 Hz, 1H), 0.75 (d, J=11.4 Hz, 1H). m/z=330.2

B388: 1-cyclohexyl-N-(2-((2-iodobenzyl)oxy)benzyl)propan-2-amine

1-cyclohexylpropan-2-amine (0.5 mmol), 2-((2-iodobenzyl)oxy)benzaldehyde(0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours;then the mixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for4 hours. The mixture was heated for 2 hours at 60° C.; then 3 ml ofmethanol and 0.2 g of C-18 chromatographic phase were added, stirred for2 hours, filtered, evaporated. The residue was purified using HPLC.Yield: 39%.

1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.32-7.19 (m, 3H), 7.04 (t, J=7.7 Hz,1H), 6.99-6.89 (m, 2H), 5.07 (s, 2H), 3.95 (d, J=13.1 Hz, 1H), 3.82 (d,J=13.1 Hz, 1H), 2.72 (q, J=6.4 Hz, 1H), 1.60 (d, J=9.5 Hz, 5H), 1.52 (d,J=13.1 Hz, 1H), 1.35 (dt, J=13.3, 6.6 Hz, 1H), 1.18-1.02 (m, 7H), 0.80(d, J=11.4 Hz, 2H). m/z=464.2

B389: 1-cyclohexyl-N-(2-((2-methylcyclohexyl)oxy)benzyl)propan-2-amine

(2-((2-methylcyclohexyl)oxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 38%.

1H NMR (400 MHz) δ 7.24 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.94(t, J=7.2 Hz, 1H), 6.82 (t, J=7.6 Hz, 1H), 3.92 (td, J=9.6, 3.8 Hz, 1H),3.71 (ddd, J=20.0, 13.4, 4.8 Hz, 1H), 3.67-3.55 (m, 1H), 3.33 (s, 2H),2.59 (dt, J=20.5, 9.4 Hz, 1H), 2.50 (s, 1H), 2.05 (d, J=12.5 Hz, 1H),1.78 (s, 1H), 1.70-1.46 (m, 8H), 1.40 (dt, J=16.3, 10.6 Hz, 1H), 1.30(s, 6H), 1.27 (d, J=8.9 Hz, 1H), 1.28-1.02 (m, 4H), 0.97 (p, J=7.6 Hz,5H), 0.78 (t, J=14.1 Hz, 2H). m/z=344.2

B390:N-(2-(bicyclo[2.2.1]heptan-2-yloxy)benzyl)-1-cyclohexylpropan-2-amine

(2-(bicyclo[2.2.1]heptan-2-yloxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 27%.

1H NMR (400 MHz, Chloroform-d) δ 7.23-7.13 (m, 2H), 6.86 (t, J=7.4 Hz,1H), 6.76 (dd, J=8.2, 4.2 Hz, 1H), 4.61 (dt, J=8.8, 3.9 Hz, 1H), 3.85(d, J=13.0 Hz, 1H), 3.70 (dd, J=13.0, 3.5 Hz, 1H), 2.68 (h, J=6.0 Hz,1H), 2.60 (d, J=4.5 Hz, 1H), 2.29 (d, J=4.9 Hz, 1H), 2.06 (ddt, J=13.1,7.5, 4.2 Hz, 1H), 2.02-1.91 (m, 1H), 1.80 (s, 1H), 1.63 (d, J=7.1 Hz,4H), 1.56-1.42 (m, 1H), 1.39 (s, 1H), 1.36 (dd, J=6.4, 3.3 Hz, 1H), 1.29(ddd, J=33.2, 8.7, 5.1 Hz, 1H), 1.14 (ddd, J=13.0, 7.2, 3.7 Hz, 3H),1.05 (d, J=6.2 Hz, 3H), 0.91-0.72 (m, 2H). m/z=342.2

B391: 1-cyclohexyl-N-(2-((3-methylcyclohexyl)oxy)benzyl)propan-2-amine

(2-((3-methylcyclohexyl)oxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 41%.

1H NMR (400 MHz) δ 7.23 (d, J=7.2 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.95(dd, J=20.0, 8.3 Hz, 1H), 6.82 (q, J=5.6, 3.9 Hz, 1H), 4.26 (td, J=10.7,10.0, 5.3 Hz, 1H), 3.75-3.51 (m, 2H), 3.33 (s, 1H), 2.58 (tt, J=10.9,5.3 Hz, 1H), 2.50 (s, 1H), 2.05 (d, J=11.9 Hz, 1H), 1.87 (t, J=14.7 Hz,1H), 1.74 (d, J=13.8 Hz, 1H), 1.58 (d, J=14.6 Hz, 7H), 1.51 (d, J=9.3Hz, 1H), 1.44-1.25 (m, 1H), 1.28-1.03 (m, 3H), 0.91 (tdd, J=26.7, 21.1,11.6 Hz, 6H), 0.75 (d, J=11.5 Hz, 1H). m/z=344.2

B392: 1-cyclohexyl-N-(2-((2-ethylcyclohexyl)oxy)benzyl)propan-2-amine

2-((2-ethylcyclohexyl)oxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100 C for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 35%.

1H NMR (400 MHz, Chloroform-d) δ 7.24-7.13 (m, 2H), 6.85 (d, J=7.8 Hz,2H), 4.56 (s, 1H), 3.91-3.78 (m, 1H), 3.73 (t, J=13.2 Hz, 1H), 2.77-2.64(m, 1H), 2.10 (dq, J=8.0, 4.0 Hz, 1H), 1.86-1.70 (m, 2H), 1.67 (s, 1H),1.65-1.57 (m, 4H), 1.60-1.51 (m, 1H), 1.47 (dt, J=14.5, 6.5 Hz, 2H),1.34 (dhept, J=22.3, 7.5 Hz, 2H), 1.22-1.10 (m, 2H), 1.06 (d, J=6.1 Hz,3H), 0.95-0.77 (m, 5H). m/z=358.2

B393:1-cyclohexyl-N-(2-((octahydro-1H-4,7-methanoinden-5-yl)oxy)benzyl)propan-2-amine

(2-((octahydro-1H-4,7-methanoinden-5-yl)oxy)phenyl)methanamine (0.5mmol) and 1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 4 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 28%.

1H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 6.91-6.79 (m, 2H), 4.64 (dt, J=8.4, 3.7 Hz, 1H), 3.72-3.64 (m, 1H),3.58 (dd, J=13.5, 5.7 Hz, 1H), 2.63-2.50 (m, 2H), 2.33 (d, J=4.1 Hz,1H), 2.16-2.05 (m, 1H), 1.98 (d, J=4.6 Hz, 1H), 1.95-1.73 (m, 3H), 1.60(t, J=12.1 Hz, 6H), 1.50 (d, J=10.6 Hz, 2H), 1.42 (d, J=10.8 Hz, 1H),1.39-1.20 (m, 2H), 1.17 (s, 1H), 1.16-1.00 (m, 3H), 0.96 (d, J=6.2 Hz,4H), 0.82 (dp, J=28.9, 8.7 Hz, 2H). m/z=382.2

Synthesis of compounds B394, B395, B396, and B404 was performedaccording to the following general scheme.

Amine 1 (0.5 mmol) and ketone 2 (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 4 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yields: 29-44%.

B394: 1-cyclohexyl-N-(2-((4-methylcyclohexyl)oxy)benzyl)propan-2-amine

1H NMR (400 MHz) δ 7.24 (t, J=6.9 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.95(dd, J=13.9, 8.2 Hz, 1H), 6.83 (t, J=7.5 Hz, 1H), 4.23 (tt, J=10.2, 4.4Hz, 1H), 3.76-3.52 (m, 2H), 3.33 (s, 1H), 2.59 (dq, J=18.5, 6.1 Hz, 1H),2.50 (s, 1H), 2.08-2.00 (m, 2H), 1.90 (d, J=14.0 Hz, 1H), 1.75-1.67 (m,2H), 1.59 (s, 3H), 1.58-1.53 (m, 4H), 1.53-1.44 (m, 1H), 1.38 (t, J=11.1Hz, 1H), 1.29 (s, 2H), 1.29-1.19 (m, 1H), 1.19-0.83 (m, 11H), 0.83-0.71(m, 2H). m/z=344.2

B395:N-(2-(bicyclo[2.2.2]octan-2-yloxy)benzyl)-1-cyclohexylpropan-2-amine

1H NMR (400 MHz, DMSO-d6) δ 17.91 (s, 1H), 7.24 (d, J=7.4 Hz, 1H), 7.15(t, J=7.8 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.82 (t, J=7.4 Hz, 1H), 4.52(d, J=9.1 Hz, 1H), 3.76-3.66 (m, 1H), 3.59 (t, J=13.2 Hz, 1H), 2.59 (p,J=6.3 Hz, 1H), 2.08 (t, J=11.7 Hz, 1H), 1.95-1.80 (m, 2H), 1.67-1.36 (m,14H), 1.25 (tt, J=8.3, 4.5 Hz, 2H), 1.19-0.93 (m, 6H), 0.77 (dq, J=22.3,11.0 Hz, 2H); m/z=356.2

B396:1-cyclohexyl-N-(2-((4,4-difluorocyclohexyl)oxy)benzyl)propan-2-amine

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=7.4 Hz, 1H), 7.19 (t, J=7.8 Hz,1H), 7.02 (d, J=8.2 Hz, 1H), 6.88 (t, J=7.4 Hz, 1H), 4.69-4.62 (m, 1H),3.69 (d, J=13.3 Hz, 1H), 3.60 (d, J=13.3 Hz, 1H), 2.60 (q, J=6.3 Hz,1H), 2.01 (s, 6H), 1.89 (dt, J=8.6, 3.9 Hz, 4H), 1.59 (d, J=10.8 Hz,5H), 1.50 (d, J=15.8 Hz, 1H), 1.28 (dq, J=13.1, 6.6, 5.9 Hz, 2H),1.21-1.11 (m, 2H), 1.14-1.08 (m, 1H), 1.08-1.01 (m, 1H), 0.97 (d, J=6.1Hz, 3H), 0.79 (p, J=12.5 Hz, 2H). m/z=366.2

B404:N-(2-(((1R,3S,5r,7r)-adamantan-2-yl)oxy)benzyl)-1-cyclohexylpropan-2-amine

1H NMR (400 MHz, DMSO-d6) δ 7.25 (dd, J=7.4, 1.8 Hz, 1H), 7.14 (td,J=7.8, 1.8 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.3 Hz, 1H), 4.53(d, J=3.3 Hz, 1H), 3.75 (d, J=13.3 Hz, 1H), 3.64 (d, J=13.3 Hz, 1H),2.61 (q, J=6.2 Hz, 1H), 2.06 (d, J=17.7 Hz, 4H), 1.82 (s, 6H), 1.71 (s,2H), 1.57 (q, J=13.8 Hz, 8H), 1.25 (dt, J=13.1, 6.0 Hz, 2H), 1.10 (dt,J=17.7, 10.5 Hz, 3H), 1.06-0.92 (m, 3H), 0.78 (dt, J=21.3, 10.5 Hz, 2H).m/z=382.2

B397:2-(((1-cyclohexylpropan-2-yl)amino)methyl)-N-(2-fluorobenzyl)anilinedihydrochloride

Step A:

tert-butyl (2-aminobenzyl)(1-cyclohexylpropan-2-yl)carbamate (1 mmol)and 2-fluorobenzaldehyde (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100 C for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C., then cooled and filtered.

Step B:

To a solution of tert-butyl(1-cyclohexylpropan-2-yl)(2-((2-fluorobenzyl)amino)benzyl)carbamate (0.5mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid(2.5 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h, and then 1N NaOH was added. The mixture wasextracted with dichloromethane, and the organic layer was washed withbrine, dried (Na₂SO₄), and filtered. The solvent was evaporated and theresidue was purified by HPLC. Yield: 27%. 1H NMR (400 MHz, DMSO-d6) δ9.16 (s, 1H), 8.97 (s, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.32 (dd, J=19.2,7.4 Hz, 2H), 7.19 (t, J=9.5 Hz, 1H), 7.13 (t, J=7.6 Hz, 2H), 6.64 (t,J=7.4 Hz, 1H), 6.54-6.45 (m, 2H), 4.39 (s, 2H), 4.14 (s, 2H), 1.73 (s,1H), 1.62 (t, J=14.0 Hz, 5H), 1.45-1.37 (m, 2H), 1.32 (d, J=6.3 Hz, 3H),1.22 (s, 2H), 1.18-1.11 (m, 3H), 0.92 (d, J=11.9 Hz, 1H), 0.84-0.77 (m,2H). m/z=355.2

B398:N-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-2-fluorobenzamidehydrochloride

Step A:

tert-butyl (2-aminobenzyl)(1-cyclohexylpropan-2-yl)carbamate (0.5 mmol)and CDI (1 mmol) were dissolved in 0.6 ml CH₃CN; the mixture was kept ata temperature of 70° C. for 1 hour, then the 2-fluorobenzoic acid (0.5mmol) was added. The mixture was heated for 2 hours at 70° C., thenfiltered, evaporated. The residue was purified by HPLC.

Step B:

To a solution of tert-butyl(1-cyclohexylpropan-2-yl)(2-(2-fluorobenzamido)benzyl)carbamate (0.5mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid(2.5 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h; then 1N NaOH was added. The mixture was extractedwith dichloromethane, and the organic layer was washed with brine, dried(Na₂SO₄), and filtered. The solvent was evaporated, and the residue waspurified by HPLC. Yield: 24%.

1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.31 (s, 1H), 9.07 (d, J=14.5Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.65-7.57 (m,1H), 7.49 (s, 2H), 7.37 (t, J=9.0 Hz, 3H), 4.11 (s, 2H), 1.62 (d, J=13.4Hz, 6H), 1.40 (s, 1H), 1.36 (d, J=11.8 Hz, 1H), 1.29 (d, J=6.3 Hz, 2H),1.13 (dd, J=23.8, 12.8 Hz, 3H), 0.92-0.76 (m, 2H). m/z=369.2

B405: 1-cyclohexyl-N-(2-(2-fluorophenoxy)benzyl)propan-2-amine

(2-(2-fluorophenoxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; then 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 28%. m/z=342.2

B406: 3-(((2-cyclohexylethyl)amino)methyl)-N-methylaniline

Step A:

tert-butyl (3-(aminomethyl)phenyl)(methyl)carbamate (1 mmol) and2-cyclohexylacetaldehyde (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 80° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C., then cooled and filtered. Yield: 43%.

Step B:

To a solution of tert-butyl (3-(((2-cyclohexylethyl)amino)methyl)phenyl)(methyl)carbamate (0.5 mmol) in dichloromethane (5 mL) wasslowly added trifluoroacetic acid (2.5 mmol) at 0° C. The reaction wasstirred at room temperature for 5 h, and then 1N NaOH was added. Themixture was extracted with dichloromethane, and the organic layer waswashed with brine, dried (Na₂SO₄), and filtered. The solvent wasevaporated, and the residue was purified by HPLC. Yield: 23%. 1H NMR(400 MHz, DMSO-d6) δ 6.98 (t, J=7.7 Hz, 1H), 6.51-6.43 (m, 2H), 6.36(dd, J=7.9, 2.4 Hz, 1H), 5.46 (d, J=6.3 Hz, 1H), 3.54 (s, 2H), 2.64 (d,J=5.0 Hz, 3H), 2.54-2.43 (m, 3H), 1.63 (d, J=12.4 Hz, 5H), 1.29 (t,J=5.7 Hz, 3H), 1.24-1.05 (m, 3H), 0.84 (q, J=11.1 Hz, 2H). m/z=247.2

B407:5-(((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)thio)methyl)-3-methyloxazolidin-2-one

1-cyclohexylpropan-2-amine (0.5 mmol) and2-(((3-methyl-2-oxooxazolidin-5-yl)methyl)thio)benzaldehyde (0.5 mmol)were dissolved in 0.6 ml MeOH, heated at 100° C. for 4 hours; then themixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C.; 3 ml of methanol and 0.2 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated. The residue was purified by HPLC. Yield: 31%.

1H NMR (400 MHz, Chloroform-d) δ 7.39 (dt, J=6.4, 1.8 Hz, 1H), 7.34 (d,J=5.7 Hz, 1H), 7.27-7.18 (m, 3H), 4.53 (ddd, J=9.2, 4.8, 2.6 Hz, 1H),3.92 (d, J=13.0 Hz, 1H), 3.85-3.78 (m, 1H), 3.63 (t, J=8.7 Hz, 1H), 3.35(ddd, J=9.4, 7.5, 3.9 Hz, 2H), 3.01 (ddd, J=13.5, 8.8, 4.5 Hz, 1H), 2.85(d, J=1.7 Hz, 3H), 2.77-2.68 (m, 1H), 1.33 (s, 3H), 1.22 (d, J=11.8 Hz,1H), 1.14 (d, J=11.0 Hz, 4H), 1.07 (dd, J=6.2, 1.7 Hz, 3H), 0.84 (s,2H). m/z=377.2

B408: 1-cyclohexyl-N-(2-((4-fluorobenzyl)oxy)benzyl)propan-2-amine

1-cyclohexylpropan-2-amine (0.5 mmol) and2-((4-fluorobenzyl)oxy)benzaldehyde (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 4 hours. The mixture was heated for2 hours at 60° C.; then 3 ml of methanol and 0.2 g of C-18chromatographic phase were added, stirred for 2 hours, filtered,evaporated. The residue was purified by HPLC. Yield: 45%.

1H NMR (400 MHz, DMSO-d6) δ 7.46 (t, J=6.7 Hz, 2H), 7.24 (d, J=7.5 Hz,1H), 7.14 (d, J=8.3 Hz, 1H), 7.09 (t, J=8.7 Hz, 2H), 6.93 (d, J=8.2 Hz,1H), 6.86 (t, J=7.5 Hz, 1H), 5.07 (s, 2H), 3.76 (d, J=13.4 Hz, 1H), 3.65(d, J=13.3 Hz, 1H), 2.62 (s, 1H), 1.62 (s, 4H), 1.54 (s, 1H), 1.25 (d,J=9.4 Hz, 2H), 1.12 (s, 4H), 1.05 (d, J=6.9 Hz, 1H), 0.97 (d, J=6.1 Hz,3H), 0.78 (s, 3H). m/z=356.2

B409: N-(2-(benzyloxy)benzyl)-1-cyclohexylpropan-2-amine

1-cyclohexylpropan-2-amine (0.5 mmol) and 2-(benzyloxy)benzaldehyde (0.5mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours; thenthe mixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4hours. The mixture was heated for 2 hours at 60° C.; then 3 ml ofmethanol and 0.2 g of C-18 chromatographic phase were added, stirred for2 hours, filtered, evaporated. The residue was purified by HPLC. Yield:39%. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=7.3 Hz, 2H), 7.36 (t, J=7.4Hz, 2H), 7.32-7.26 (m, 1H), 7.24 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 6.94 (d, J=8.2 Hz, 1H), 6.86 (t, J=7.4 Hz, 1H), 5.10 (s, 2H), 3.78(d, J=13.6 Hz, 1H), 3.66 (d, J=13.5 Hz, 1H), 2.63 (s, 1H), 1.60 (d,J=12.0 Hz, 5H), 1.26 (d, J=10.3 Hz, 2H), 1.12 (s, 5H), 0.97 (d, J=6.1Hz, 2H), 0.80 (d, J=12.3 Hz, 2H). m/z=338.2

B410: 2-(2-(tetrahydro-2H-thiopyran-4-yl)ethyl)-1,4-dihydroisoquinolin-3(2H)-one

2-(tetrahydro-2H-thiopyran-4-yl)ethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF,and DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5h, cooled; solvent was removed by evaporation and residue was purifiedby HPLC. Yield: 31%.

1H NMR (400 MHz, DMSO-d6) δ 7.23 (qd, J=10.9, 9.9, 5.4 Hz, 2H), 4.46 (s,1H), 3.50 (s, 1H), 3.43 (t, J=7.4 Hz, 1H), 2.58-2.51 (m, 2H), 1.99 (d,J=9.9 Hz, 1H), 1.42 (s, 1H), 1.26 (s, 2H). m/z=276.0

B411: 2-(2-(cyclohex-1-en-1-yl)ethyl)-1,4-dihydroisoquinolin-3 (2H)-one

2-(cyclohex-1-en-1-yl)ethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF,and DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5h, cooled; the solvent was removed by evaporation, and the residue waspurified by HPLC. Yield: 37%. 1H NMR (400 MHz, DMSO-d6) δ 7.23 (p, J=8.0Hz, 2H), 5.32 (s, 0H), 4.46 (s, 1H), 3.32 (s, 1H), 2.12 (t, J=7.3 Hz,1H), 1.94 (s, 1H), 1.84 (s, 1H), 1.53 (q, J=6.3, 5.7 Hz, 1H), 1.46 (d,J=6.5 Hz, 1H). m/z=256.2

B412: 2-(1-cyclohexylpropan-2-yl)-1,4-dihydroisoquinolin-3 (2H)-one

1-cyclohexylpropan-2-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation and residue was purified byHPLC. Yield: 47%. Yellow gum.

1H NMR (400 MHz, DMSO-d6) δ 7.36-7.30 (m, 1H), 7.23 (p, J=4.7 Hz, 3H),4.72 (dt, J=9.8, 6.2 Hz, 1H), 4.32 (d, J=15.5 Hz, 1H), 4.25 (d, J=15.4Hz, 1H), 3.51 (s, 2H), 1.74 (d, J=12.8 Hz, 1H), 1.61-1.42 (m, 5H), 1.24(ddd, J=14.0, 8.5, 5.5 Hz, 1H), 1.05 (d, J=6.8 Hz, 4H), 1.01 (s, 3H),0.79 (dt, J=23.0, 11.9 Hz, 2H). m/z=272.2

B413: 2-(2-cyclohexylpropyl)-1,4-dihydroisoquinolin-3 (2H)-one

2-cyclohexylpropan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation, and residue was purified byHPLC. Yield: 39%. 1H NMR (400 MHz, DMSO-d6) δ 7.26 (dd, J=13.9, 6.6 Hz,1H), 7.22 (t, J=5.3 Hz, 1H), 4.43 (d, J=2.7 Hz, 1H), 3.52 (s, 1H),3.42-3.23 (m, 1H), 1.63 (dq, J=49.9, 12.8, 11.0 Hz, 3H), 1.16 (d, J=11.8Hz, 1H), 1.13-1.04 (m, 1H), 0.72 (d, J=6.8 Hz, 1H). m/z=272.2

B414:(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methanesulfonamide

(2-(aminomethyl)phenyl)methanesulfonamide (0.5 mmol) and1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 51%.

1H NMR (400 MHz, Chloroform-d) δ 7.53-7.47 (m, 1H), 7.35 (q, J=6.3, 5.2Hz, 3H), 4.55 (s, 2H), 3.95 (d, J=12.3 Hz, 1H), 3.82 (d, J=12.3 Hz, 1H),2.92 (q, J=6.8 Hz, 1H), 1.69 (d, J=11.7 Hz, 4H), 1.64 (s, 1H), 1.43 (dt,J=13.0, 6.5 Hz, 1H), 1.30 (s, 1H), 1.24 (d, J=11.7 Hz, 1H), 1.22 (s,2H), 1.18 (t, J=6.2 Hz, 4H), 0.99-0.89 (m, 1H), 0.87 (d, J=11.0 Hz, 1H).m/z=325.2

B415: 2-(2-(2-methylcyclohexyl)ethyl)-1,4-dihydroisoquinolin-3 (2H)-one

2-(2-methylcyclohexyl)ethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF,and DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5h, cooled; solvent was removed by evaporation, and the residue waspurified by HPLC. Yield: 45%.

1H NMR (400 MHz, DMSO-d6) δ 7.23 (p, J=8.0 Hz, 2H), 5.32 (s, 0H), 4.46(s, 1H), 3.32 (s, 1H), 2.12 (t, J=7.3 Hz, 1H), 1.94 (s, 1H), 1.84 (s,1H), 1.53 (q, J=6.3, 5.7 Hz, 1H), 1.46 (d, J=6.5 Hz, 1H). m/z=272.2

B416: 2-(3-cyclohexylpropyl)-1,4-dihydroisoquinolin-3 (2H)-one

2-cyclohexylethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation and residue was purified byHPLC. Yield: 31%.

1H NMR (400 MHz, Chloroform-d) δ 7.28-7.20 (m, 1H), 7.17 (t, J=6.5 Hz,1H), 4.45 (s, 1H), 3.60 (s, 1H), 3.48 (t, J=7.6 Hz, 1H), 1.73-1.56 (m,4H), 1.27-1.05 (m, 3H), 0.87 (t, J=11.3 Hz, 1H). m/z=272.2

B417: 2-(2-cyclohexylethyl)-1,2,3,4-tetrahydroisoquinoline

1,2,3,4-tetrahydroisoquinoline (0.5 mmol) and 2-cyclohexylacetaldehyde(0.5 mmol) were dissolved in 0.6 ml CHCl₃; NaBH(OAc)₃ (1.5 mmol) wasadded and stirred for 4 hours. The mixture was heated for 12 hours at60° C.; then 3 ml of methanol and 0.2 g of C-18 chromatographic phasewere added, stirred for 2 hours, filtered, evaporated and dissolved in0.5 ml of DMSO. The residue was purified by HPLC. Yield: 51%.

1H NMR (400 MHz, Chloroform-d) δ 7.10 (dq, J=9.7, 5.6, 4.9 Hz, 3H),7.05-6.98 (m, 1H), 3.62 (s, 2H), 2.91 (t, J=6.0 Hz, 2H), 2.72 (t, J=5.9Hz, 2H), 2.56-2.48 (m, 2H), 1.78-1.61 (m, 5H), 1.50 (q, J=7.0 Hz, 2H),1.36-1.12 (m, 2H), 0.95 (q, J=11.0 Hz, 2H). m/z=244.2

B418: 2-cyclohexyl-1,4-dihydroisoquinolin-3 (2H)-one

Cyclohexanamine (0.5 mmol) and methyl 2-(2-(chloromethyl)phenyl)acetate(0.5 mmol) were mixed in 5 ml of DMF; DIPEA (0.75 mmol) was added. Themixture was heated at 80° C. for 5 h, cooled; solvent was removed byevaporation, and residue was purified by HPLC. Yield: 47%.

1H NMR (400 MHz, Chloroform-d) δ 7.28-7.14 (m, 4H), 4.55 (ddq, J=11.8,7.5, 3.8 Hz, 1H), 4.34 (s, 2H), 3.60 (s, 2H), 1.82 (d, J=10.5 Hz, 2H),1.71 (d, J=4.1 Hz, 1H), 1.45 (hd, J=12.4, 3.2 Hz, 4H), 1.15 (tt, J=10.3,4.6 Hz, 1H). m/z=230.2

B419: 2-(2-cyclohexylethyl)isoindolin-1-one

2-cyclohexylethan-1-amine (0.5 mmol) and methyl 2-formylbenzoate (0.5mmol) were dissolved in 0.6 ml isopropanol, heated at 80° C. for 2hours; then the mixture was cooled, NaBH₄ (0.5 mmol) was added andstirred for 4 hours. Then 0.2 g of C-18 chromatographic phase was added,stirred for 2 hours, filtered, evaporated. The residue was purified byHPLC. Yield: 41%.

1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J=7.5 Hz, 1H), 7.57 (d, J=4.2 Hz,2H), 7.46 (dp, J=8.5, 4.2 Hz, 1H), 4.44 (s, 2H), 3.53 (t, J=7.3 Hz, 2H),1.78-1.69 (m, 2H), 1.60 (dt, J=17.9, 6.0 Hz, 3H), 1.48 (q, J=7.1 Hz,2H), 1.27-1.12 (m, 3H), 1.10 (dd, J=15.1, 3.6 Hz, 1H), 0.90 (tt, J=12.0,6.0 Hz, 2H). m/z=244.2

B420: 2-cyclohexyl-N-(3-((methylamino)methyl)benzyl)ethan-1-amine

Step A:

tert-butyl (3-(aminomethyl)phenyl)(methyl)carbamate (1 mmol) and2-cyclohexylacetaldehyde (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 80° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C.; then cooled and filtered. Yield: 510%.

Step B:

To a solution of tert-butyl(3-(((2-cyclohexylethyl)amino)methyl)phenyl)(methyl) carbamate (0.5mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid(2.5 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h, and then 1 N NaOH was added. The mixture wasextracted with dichloromethane, and the organic layer was washed withbrine, dried (Na₂SO₄), and filtered. The solvent was evaporated and theresidue was purified by HPLC. Yield: 31%.

1H NMR (400 MHz, DMSO-d6) δ 7.26-7.18 (m, 2H), 7.14 (d, J=7.4 Hz, 2H),3.62 (d, J=16.2 Hz, 4H), 2.95 (s, 1H), 2.46 (d, J=7.0 Hz, 2H), 2.24 (s,3H), 1.63 (d, J=12.3 Hz, 5H), 1.30 (t, J=6.1 Hz, 3H), 1.18 (d, J=11.9Hz, 1H), 1.12 (d, J=9.7 Hz, 2H), 0.90-0.80 (m, 2H). m/z=261.2

B421: 2-phenethyl-1,4-dihydroisoquinolin-3 (2H)-one

2-phenylethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation and residue was purified byHPLC. Yield: 51%.

¹H NMR (400 MHz, Chloroform-d) δ 7.31-7.16 (m, 6H), 7.16 (d, J=7.5 Hz,1H), 7.04 (d, J=7.4 Hz, 1H), 4.29 (s, 2H), 3.75 (t, J=7.4 Hz, 2H), 3.60(s, 2H), 2.92 (t, J=7.4 Hz, 2H). m/z=252.2

B422: 2-(2-cycloheptylethyl)-1,4-dihydroisoquinolin-3 (2H)-one

Methyl 2-(2-(aminomethyl)phenyl)acetate (0.5 mmol) and2-cycloheptylacetaldehyde (0.5 mmol) were dissolved in 0.6 mlisopropanol, heated at 80° C. for 2 hours; then the mixture was cooled,NaBH₄ (0.5 mmol) was added and stirred for 4 hours. Then 0.2 g of C-18chromatographic phase was added, stirred for 2 hours, filtered,evaporated. The residue was purified by HPLC. Yield: 34%.

1H NMR (400 MHz, Chloroform-d) δ 7.23 (dd, J=12.7, 6.9 Hz, 1H), 7.17 (t,J=6.7 Hz, 1H), 4.45 (s, 1H), 3.60 (s, 1H), 3.52 (t, J=7.5 Hz, 1H), 1.73(ddt, J=13.4, 6.5, 3.1 Hz, 1H), 1.64 (ddd, J=17.1, 8.6, 5.3 Hz, 1H),1.56-1.45 (m, 1H), 1.39 (dd, J=12.4, 9.6 Hz, 0H), 1.23 (ddt, J=13.4,9.4, 4.8 Hz, 1H). m/z=272.2

B423: N-((1-benzyl-1H-indol-7-yl)methyl)-1-cyclohexylpropan-2-amine

1-cyclohexylpropan-2-amine (0.5 mmol) and1-benzyl-1H-indole-7-carbaldehyde (0.55 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 4 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated and theresidue was purified by HPLC. Yield: 34%.

1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J=6.4, 2.8 Hz, 1H), 7.37 (d, J=3.2Hz, 1H), 7.27 (t, J=7.4 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 6.95 (q, J=4.0,3.4 Hz, 2H), 6.80 (d, J=7.5 Hz, 2H), 6.53 (d, J=3.1 Hz, 1H), 5.92 (d,J=17.1 Hz, 1H), 5.85 (d, J=17.1 Hz, 1H), 3.74 (d, J=11.8 Hz, 1H), 3.33(s, 1H), 2.61 (s, 1H), 1.64-1.49 (m, 5H), 1.46 (s, 1H), 1.37 (s, 1H),1.27 (dt, J=13.6, 6.9 Hz, 1H), 1.16 (d, J=12.3 Hz, 1H), 1.11 (s, 1H),1.10-1.02 (m, 1H), 1.05-0.94 (m, 3H), 0.76 (p, J=11.6 Hz, 2H). m/z=361.4

B424: 1-cyclohexyl-N-(2-((methylsulfonyl)methyl)benzyl)propan-2-amine

(2-((methylsulfonyl)methyl)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 49%.

1H NMR (400 MHz, DMSO-d6) δ 7.42-7.36 (m, 1H), 7.34 (d, J=7.1 Hz, 1H),7.26 (p, J=7.2 Hz, 2H), 4.72 (d, J=13.8 Hz, 1H), 4.63 (d, J=13.9 Hz,1H), 3.92 (d, J=12.6 Hz, 1H), 3.76 (d, J=12.7 Hz, 1H), 3.03 (s, 1H),2.89 (d, J=2.3 Hz, 3H), 2.68 (s, 1H), 2.50 (s, 1H), 1.66 (d, J=11.5 Hz,5H), 1.38-1.22 (m, 2H), 1.20 (s, 1H), 1.17 (s, 1H), 1.11 (s, 1H), 1.05(dd, J=6.2, 2.2 Hz, 3H), 0.90-0.79 (m, 2H). m/z=324.2

B425: 2-(2-cyclohexylethyl)-1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one

Under argon, into a reaction vessel of1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one (0.5 mmol), potassium iodide0.70 g (0.4 mmol), potassium carbonate 0.70 g (0.5 mmol), DMF (1 mL) and(2-chloroethyl)cyclohexane (0.5 mmol) were added. The reaction vesselwas heated to 80° C., and the mixture was stirred for 12 hours. Thereaction vessel was cooled to room temperature, ethyl acetate 20 mL wasadded, the organic layer was washed with water 50 mL, saturated brine 50mL. Product was purified by HPLC. Yield: 80%.

1H NMR (400 MHz, Chloroform-d) δ 7.27 (d, J=7.3 Hz, 1H), 7.17 (dd,J=10.5, 6.4 Hz, 3H), 3.97 (s, 2H), 3.74 (s, 0H), 2.69 (s, 2H), 2.24 (d,J=6.3 Hz, 2H), 2.14 (s, 2H), 1.65 (td, J=10.2, 4.6 Hz, 6H), 1.41 (q,J=7.6 Hz, 2H), 1.28-1.05 (m, 4H), 0.93-0.79 (m, 2H). m/z=272.2

B426:3-(1-cyclohexylpropan-2-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one

Step A:

1-cyclohexylpropan-2-amine (1.0 mmol) and 2-hydroxybenzaldehyde (1.0mmol) were dissolved in 1 ml MeOH, heated at 100° C. for 2 hours; thenthe mixture was cooled, NaBH(OAc)₃ (1.5 mmol) was added and stirred for4 hours. The mixture was heated for 2 hours at 60° C.; 5 ml of methanoland 0.3 g of C-18 chromatographic phase were added, stirred for 2 hours,filtered, evaporated. The residue was purified by HPLC. Yield: 58%.

Step B:

2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenol (0.5 mmol) and Boc₂O(0.6 mmol) in THF (1 mL) were heated for 2 h at 50° C. Then Et₃N (0.1mL) was added, and the mixture was heated for 1 hour at 50° C. Thesolvent was evaporated, the residue was purified by LC. Yield: 41%.

1H NMR (400 MHz, DMSO-d6) δ 7.34-7.25 (m, 2H), 7.14 (t, J=7.4 Hz, 1H),7.02 (d, J=8.3 Hz, 1H), 4.50-4.35 (m, 2H), 4.31 (d, J=15.0 Hz, 1H), 1.78(d, J=12.8 Hz, 1H), 1.65-1.51 (m, 5H), 1.28 (ddd, J=14.0, 8.5, 5.6 Hz,1H), 1.13 (dd, J=16.8, 7.6 Hz, 7H), 0.87 (dt, J=23.3, 12.1 Hz, 2H).m/z=274.2

B427: 2-(2-cyclopentylethyl)-1,4-dihydroisoquinolin-3 (2H)-one

2-cyclopentylethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation and residue was purified byHPLC. Yield: 29%.

1H NMR (400 MHz, Chloroform-d) δ 7.28-7.21 (m, 1H), 7.18 (q, J=9.0, 6.8Hz, 1H), 4.46 (s, 1H), 3.60 (s, 1H), 3.52 (dd, J=8.8, 6.6 Hz, 1H), 1.79(td, J=13.1, 11.9, 7.1 Hz, 1H), 1.66-1.53 (m, 2H), 1.52 (t, J=6.6 Hz,1H), 1.20-1.11 (m, 1H). m/z=243

B428:(2S)-2-amino-N-((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)-4-methylpentanamidedihydrochloride

Step A:

tert-butyl (1-cyclohexylpropan-2-yl)(2-(sulfamoylmethyl)benzyl)carbamate(2 mmol) and CDI (4 mmol) were dissolved in 1.2 ml CH₃CN; the mixturewas kept at a temperature of 70° C. for 1 hour, then(tert-butoxycarbonyl)-L-leucine (2 mmol) was added. The mixture washeated for 2 hours at 70° C., then filtered, evaporated. The residue waspurified by HPLC.

Step B:

To a solution of tert-butyl(2-((N-((tert-butoxycarbonyl)-L-leucyl)sulfamoyl)methyl)benzyl)(1-cyclohexylpropan-2-yl)carbamate(1 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid(5 mmol) at 0° C. The reaction solution was stirred at room temperaturefor 5 h, and then 1N NaOH was added. The mixture was extracted withdichloromethane, and the organic layer was washed with brine, dried(Na₂SO₄), and filtered. The solvent was evaporated, and the residue waspurified by HPLC. Yield: 31%.

1H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J=7.3 Hz, 1H), 7.33 (dt,J=24.0, 7.5 Hz, 3H), 5.20 (s, 4H), 4.48 (s, 2H), 4.08 (s, 2H), 3.39 (s,1H), 3.24 (s, 1H), 2.56 (s, 1H), 1.63 (d, J=15.6 Hz, 6H), 1.41 (t,J=11.1 Hz, 1H), 1.27 (d, J=5.6 Hz, 3H), 1.17 (dd, J=22.8, 11.2 Hz, 2H),0.93 (dd, J=13.7, 5.1 Hz, 5H), 0.86 (s, 3H), 0.35 (s, 1H). m/z=438.2

B429: 1-cyclohexyl-N-(2-(2-fluorophenethoxy)benzyl)propan-2-amine

1-cyclohexylpropan-2-amine (0.5 mmol) and2-(2-fluorophenethoxy)benzaldehyde (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 4 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 31%.

1H NMR (400 MHz, DMSO-d6) δ 7.42 (dt, J=8.9, 4.3 Hz, 1H), 7.34-7.24 (m,1H), 7.28-7.10 (m, 4H), 6.95 (d, J=8.1 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H),4.26-4.12 (m, 2H), 3.63 (d, J=14.0 Hz, 1H), 3.48 (d, J=14.0 Hz, 1H),3.09 (t, J=6.3 Hz, 2H), 2.54 (s, 1H), 2.49-2.42 (m, 1H), 1.56 (d, J=12.7Hz, 4H), 1.49 (s, 1H), 1.40 (d, J=13.1 Hz, 1H), 1.16 (dd, J=9.4, 6.4 Hz,1H), 1.14 (s, 2H), 1.08 (t, J=8.1 Hz, 3H), 0.95 (p, J=3.8 Hz, 1H), 0.88(d, J=6.1 Hz, 3H), 0.73 (dt, J=23.4, 11.2 Hz, 2H). m/z=370.2

B430: 2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,4-dihydroisoquinolin-3(2H)-one

2-(tetrahydro-2H-pyran-4-yl)ethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation and residue was purified byHPLC. Yield: 410%.

1H NMR (400 MHz, Chloroform-d) δ 7.62 (ddt, J=16.3, 11.9, 5.3 Hz, 3H),4.87 (s, 2H), 4.27-4.18 (m, 2H), 3.88 (d, J=8.7 Hz, 4H), 3.66 (td,J=11.7, 2.0 Hz, 2H), 3.56 (s, 2H), 2.91 (dd, J=3.8, 1.9 Hz, 1H), 2.05(d, J=12.9 Hz, 2H), 1.88 (t, J=6.4 Hz, 3H), 1.68-1.57 (m, 2H). m/z=260.2

B431:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-(2,3-dihydroxypropyl)methanesulfonamide

1-(2-(aminomethyl)phenyl)-N-(2,3-dihydroxypropyl)methanesulfonamide (0.5mmol) and 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 5 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 38%.

1H NMR (400 MHz, DMSO-d6) δ 7.34 (t, J=7.5 Hz, 2H), 7.27 (q, J=7.6, 7.1Hz, 2H), 7.04 (s, 1H), 4.80 (d, J=4.9 Hz, 1H), 4.61 (dd, J=13.9, 10.8Hz, 1H), 4.52 (dd, J=18.3, 9.2 Hz, 2H), 3.88 (d, J=13.0 Hz, 1H), 3.74(d, J=12.8 Hz, 1H), 3.48 (s, 1H), 2.99 (s, 1H), 2.83 (d, J=5.8 Hz, 1H),2.63 (s, 1H), 2.54 (s, 2H), 1.60 (s, 6H), 1.32 (d, J=16.0 Hz, 2H),1.22-1.11 (m, 1H), 1.09-0.98 (m, 3H), 0.81 (t, J=12.2 Hz, 2H). m/z=399.1

B432:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-(1-methylpiperidin-4-yl)methanesulfonamide

1-(2-(aminomethyl)phenyl)-N-(1-methylpiperidin-4-yl)methanesulfonamide(0.5 mmol), 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 5 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified using HPLC. Yield: 42%.

1H NMR (400 MHz, DMSO-d6) δ 7.37-7.23 (m, 3H), 7.23 (s, 1H), 7.27-7.17(m, 1H), 4.60 (d, J=13.8 Hz, 1H), 4.46 (d, J=13.7 Hz, 1H), 3.88 (d,J=12.8 Hz, 1H), 3.76 (d, J=12.7 Hz, 1H), 2.95 (s, 1H), 2.65 (t, J=11.7Hz, 3H), 2.54 (s, 1H), 2.09 (d, J=11.7 Hz, 3H), 1.81 (dd, J=24.7, 13.5Hz, 3H), 1.73 (s, 1H), 1.62 (d, J=13.7 Hz, 5H), 1.50-1.27 (m, 3H),1.25-1.09 (m, 2H), 1.09-0.98 (m, 3H), 0.87-0.77 (m, 2H). m/z=422.1

B433:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-((tetrahydrofuran-2-yl)methyl)methanesulfonamide

1-(2-(aminomethyl)phenyl)-N-((tetrahydrofuran-2-yl)methyl)methanesulfonamide(0.5 mmol) and 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6ml MeOH, heated at 100° C. for 3 hours; then the mixture was cooled,NaBH₄ (0.5 mmol) was added and stirred for 5 hours. The mixture washeated for 2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18chromatographic phase were added, stirred for 2 hours, filtered,evaporated. The residue was purified by HPLC. Yield: 34%.

1H NMR (400 MHz, DMSO-d6) δ 7.29 (dddd, J=28.1, 14.5, 7.5, 3.9 Hz, 5H),4.61 (dd, J=13.9, 10.2 Hz, 1H), 4.50 (dd, J=13.8, 7.9 Hz, 1H), 3.88 (dd,J=12.9, 3.0 Hz, 1H), 3.81 (p, J=6.1 Hz, 1H), 3.79-3.69 (m, 2H), 3.61 (q,J=7.2 Hz, 1H), 2.89 (t, J=5.9 Hz, 2H), 2.63 (q, J=6.4 Hz, 1H), 2.54 (s,1H), 1.86 (dq, J=11.7, 7.0 Hz, 1H), 1.84-1.73 (m, 2H), 1.65-1.57 (m,4H), 1.54 (dt, J=10.5, 7.1 Hz, 2H), 1.33 (tt, J=13.5, 6.0 Hz, 2H), 1.14(ddd, J=26.0, 19.5, 8.8 Hz, 4H), 1.01 (d, J=6.1 Hz, 3H), 0.83 (s, 1H),0.79 (d, J=11.8 Hz, 1H). m/z=409.2

B434:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-(2-methoxyethyl)methanesulfonamide

1-(2-(aminomethyl)phenyl)-N-(2-methoxyethyl)methanesulfonamide (0.5mmol) and 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 5 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 39%.

1H NMR (400 MHz, DMSO-d6) δ 7.38-7.20 (m, 4H), 7.30 (s, 2H), 4.61 (d,J=13.9 Hz, 1H), 4.50 (d, J=13.8 Hz, 1H), 3.88 (d, J=12.9 Hz, 1H), 3.75(d, J=12.9 Hz, 1H), 3.33 (t, J=5.8 Hz, 2H), 3.25 (s, 3H), 3.02 (t, J=5.9Hz, 2H), 2.63 (q, J=6.4 Hz, 1H), 2.54 (s, 1H), 1.61 (d, J=17.1 Hz, 1H),1.61 (s, 4H), 1.38-1.26 (m, 2H), 1.18 (d, J=12.9 Hz, 1H), 1.15-1.05 (m,1H), 1.01 (d, J=6.2 Hz, 3H), 0.86-0.75 (m, 2H). m/z=383.1

B435: methyl2-(7-(((1-cyclohexylpropan-2-yl)amino)methyl)-1H-indol-1-yl)acetatehydrochloride

Step A:

tert-butyl ((1H-indol-7-yl)methyl)(1-cyclohexylpropan-2-yl)carbamate (1mmol) was added to 10 mL of DMF. NaH (1.1 mmol) was added to thestirring solution at 0° C., and the mixture was allowed to reach r.tstirring for 20 min. Then, methyl 2-bromoacetate (1.1 mmol) was added.The reaction mixture was allowed to stir under argon for 5 h at 50° C.The reaction was quenched with water (10 mL) and extracted twice withEtOAc (20 mL). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. The crude methyl2-(7-(((tert-butoxycarbonyl)(1-cyclohexylpropan-2-yl)amino)methyl)-1H-indol-1-yl)acetatewas purified by chromatography. Yield: 71%.

Step B:

To a solution of methyl2-(7-(((tert-butoxycarbonyl)(1-cyclohexylpropan-2-yl)amino)methyl)-1H-indol-1-yl)acetate(0.5 mmol) in dichloromethane (5 mL) was slowly added trifluoroaceticacid (2.5 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h, and then 1N NaOH was added. The mixture wasextracted with dichloromethane, and the organic layer was washed withbrine, dried (Na₂SO₄), and filtered. The solvent was evaporated, and theresidue was purified by HPLC. Yield: 58%.

1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.29 (s, 1H), 7.62 (d, J=7.8Hz, 1H), 7.40-7.30 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.54 (d, J=3.2 Hz,1H), 5.38 (s, 2H), 4.31 (s, 2H), 3.72 (s, 2H), 1.75 (t, J=9.0 Hz, 1H),1.68 (d, J=13.2 Hz, 2H), 1.64 (s, 1H), 1.48 (td, J=12.8, 12.0, 7.1 Hz,1H), 1.34 (d, J=6.4 Hz, 2H), 1.20 (s, 2H), 0.97 (q, J=11.3 Hz, 1H), 0.87(s, 1H). m/z=343.2

B436: 2-(7-(((1-cyclohexylpropan-2-yl)amino)methyl)-1H-indol-1-yl)aceticacid hydrochloride

Methyl2-(7-(((1-cyclohexylpropan-2-yl)amino)methyl)-1H-indol-1-yl)acetate (0.5mmol) was dissolved in HCl (5 mmol). The reaction stirred at 50° C.overnight. The reaction was poured into water and extracted (2×) withdichloromethane. Reaction mixture was concentrated under reducedpressure. The crude residue was purified by HPLC. Yield: 26%.

1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.25(d, J=3.2 Hz, 1H), 7.11 (d, J=7.1 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 6.45(d, J=3.2 Hz, 1H), 4.85 (d, J=2.4 Hz, 2H), 4.44 (d, J=13.2 Hz, 1H), 4.33(d, J=13.2 Hz, 1H), 3.16 (s, 1H), 2.54 (s, 1H), 1.67 (d, J=12.3 Hz, 4H),1.60 (d, J=12.0 Hz, 4H), 1.23 (t, J=8.1 Hz, 4H), 1.17 (s, 7H), 0.89 (dt,J=37.0, 11.3 Hz, 3H). m/z=329.2

B437:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N,N-dimethylmethanesulfonamide

1-(2-(aminomethyl)phenyl)-N,N-dimethylmethanesulfonamide (0.5 mmol) and1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 3 hours, then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 33%.

1H NMR (400 MHz, DMSO-d6) δ 7.30 (dtd, J=27.2, 7.0, 6.5, 1.9 Hz, 4H),4.64 (d, J=13.6 Hz, 1H), 4.56 (d, J=13.7 Hz, 1H), 3.88 (d, J=12.8 Hz,1H), 3.75 (d, J=12.8 Hz, 1H), 2.79 (s, 6H), 2.64 (q, J=5.9, 5.4 Hz, 1H),1.62 (d, J=12.5 Hz, 6H), 1.38-1.27 (m, 2H), 1.25-1.03 (m, 3H), 1.01 (d,J=6.1 Hz, 3H), 0.81 (s, 2H). m/z=353.2

B438:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N—((S)-2,3-dihydroxypropyl)-N-methylmethanesulfonamide

(S)-1-(2-(aminomethyl)phenyl)-N-(2,3-dihydroxypropyl)-N-methylmethanesulfonamide(0.5 mmol), 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 5 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 27%.

1H NMR (400 MHz, DMSO-d6) δ 7.34 (s, 2H), 7.34-7.22 (m, 2H), 4.88 (d,J=5.3 Hz, 1H), 4.71-4.53 (m, 3H), 3.88 (d, J=13.0 Hz, 1H), 3.77 (s, 1H),3.63 (s, 1H), 3.19 (d, J=13.5 Hz, 1H), 3.04-2.97 (m, 1H), 2.85 (s, 2H),2.54 (s, 3H), 2.49 (s, 1H), 1.60 (s, 6H), 1.35 (s, 2H), 1.22-1.11 (m,2H), 1.07 (s, 3H), 1.01 (d, J=6.1 Hz, 2H), 0.86-0.76 (m, 2H). m/z=413.3

B439:1-cyclohexyl-N-(2-(((4-methylpiperazin-1-yl)sulfonyl)methyl)benzyl)propan-2-amine

(2-(((4-methylpiperazin-1-yl)sulfonyl)methyl)phenyl)methanamine (0.5mmol), 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 5 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 38%.

1H NMR (400 MHz, DMSO-d6) δ 7.38-7.22 (m, 4H), 4.66 (d, J=13.7 Hz, 1H),4.57 (d, J=13.7 Hz, 1H), 3.88 (d, J=12.7 Hz, 1H), 3.76 (d, J=12.7 Hz,1H), 3.18 (d, J=5.1 Hz, 4H), 2.65 (t, J=6.4 Hz, 1H), 2.54 (s, 2H), 2.36(t, J=5.0 Hz, 4H), 2.20 (s, 3H), 1.66-1.57 (m, 5H), 1.33 (dd, J=14.9,7.9 Hz, 2H), 1.25-0.98 (m, 6H), 0.83 (d, J=10.5 Hz, 2H). m/z=408.1

B440: methyl 2-(3-(((2-cyclohexylethyl)amino)methyl)phenyl)acetate

Methyl 2-(3-(aminomethyl)phenyl)acetate (0.5 mmol) and2-cyclohexylacetaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 41%.

1H NMR (400 MHz, DMSO-d6) δ 7.26-7.15 (m, 1H), 3.62 (t, J=12.3 Hz, 2H),1.66 (d, J=12.6 Hz, 1H), 1.32 (d, J=7.5 Hz, 1H), 1.16 (dt, J=22.6, 12.5Hz, 1H), 0.86 (d, J=10.3 Hz, 1H). m/z=290.1

B441: 1-cyclohexyl-N-((1-methyl-1H-indol-7-yl)methyl)propan-2-aminehydrochloride

Step A:

tert-butyl ((1H-indol-7-yl)methyl)(1-cyclohexylpropan-2-yl)carbamate (1mmol) was dissolved in 10 mL of DMF. NaH (1.1 mmol) was added to thestirring solution at 0° C., and the mixture was allowed to reach r.t.stirring for 20 min. Then CH₃I (1.1 mmol) was added. The reactionmixture was allowed to stir under argon for 5 h at 50° C. The reactionwas quenched with water (10 mL) and extracted twice with EtOAc (20 mL).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated under reduced pressure. The crude product was purifiedby chromatography. Yield: 54%.

Step B:

To a solution of tert-butyl(1-cyclohexylpropan-2-yl)((1-methyl-1H-indol-7-yl)methyl)carbamate (0.5mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid(2.5 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h, and then 1N NaOH was added. The mixture wasextracted with dichloromethane, and the organic layer was washed withbrine, dried (Na₂SO₄), and filtered. The solvent was evaporated and theresidue was purified by HPLC. Yield: 310%.

1H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J=7.8 Hz, 1H), 7.21 (d, J=3.1 Hz,1H), 6.95 (d, J=6.9 Hz, 1H), 6.91 (s, 0H), 6.89 (t, J=7.4 Hz, 1H), 6.37(d, J=3.2 Hz, 1H), 4.12 (d, J=21.9 Hz, 4H), 3.93 (d, J=12.0 Hz, 1H),2.73 (q, J=6.4 Hz, 1H), 1.60 (d, J=14.0 Hz, 4H), 1.52 (d, J=13.7 Hz,1H), 1.37 (s, 2H), 1.33 (q, J=6.7, 6.1 Hz, 1H), 1.08 (dd, J=13.3, 7.8Hz, 7H), 0.79 (dd, J=25.2, 12.5 Hz, 2H). m/z=285.2

B442:2-(7-(((1-cyclohexylpropan-2-yl)amino)methyl)-1H-indol-1-yl)ethan-1-olhydrochloride

Step A:

tert-butyl ((1H-indol-7-yl)methyl)(1-cyclohexylpropan-2-yl)carbamate (1mmol) was dissolved in 10 mL of DMF. NaH (1.1 mmol) was added to thestirring solution at 0° C., and the mixture was allowed to reach r.t.stirring for 20 min. Then 2-chloroethanol (1.1 mmol) was added. Thereaction mixture was allowed to stir under argon for 5 h at 50° C. Thereaction was quenched with water (10 mL) and extracted twice with EtOAc(20 mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure. The crude tert-butyl(1-cyclohexylpropan-2-yl)((1-(2-hydroxyethyl)-1H-indol-7-yl)methyl)carbamatewas purified by chromatography. Yield: 51%.

Step B:

To a solution of tert-butyl(1-cyclohexylpropan-2-yl)((1-(2-hydroxyethyl)-1H-indol-7-yl)methyl)carbamate(0.5 mmol) in dichloromethane (5 mL) was slowly added trifluoroaceticacid (2.5 mmol) at 0° C. The reaction solution was stirred at roomtemperature for 5 h, and then 1 N NaOH was added. The mixture wasextracted with dichloromethane, and the organic layer was washed withbrine, dried (Na₂SO₄), and filtered. The solvent was evaporated and theresidue was purified by HPLC. Yield: 27%.

1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=7.7 Hz, 1H), 7.29 (dd, J=6.7, 3.2Hz, 1H), 6.96 (d, J=6.5 Hz, 1H), 6.90 (dd, J=8.8, 6.0 Hz, 1H), 6.42 (d,J=3.2 Hz, 1H), 4.68-4.52 (m, 2H), 4.06 (t, J=11.0 Hz, 1H), 3.90 (d,J=11.8 Hz, 1H), 3.71 (dt, J=11.4, 5.6 Hz, 2H), 3.49-3.42 (m, 0H), 2.72(s, 1H), 2.54 (s, 1H), 1.59 (q, J=14.2, 13.0 Hz, 6H), 1.39-1.28 (m, 3H),1.21-1.08 (m, 3H), 1.06 (d, J=6.0 Hz, 4H), 0.83 (d, J=11.0 Hz, 1H), 0.78(d, J=10.8 Hz, 1H). m/z=315.2

B445:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-methylmethanesulfonamide

1-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide (0.5 mmol) and1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 31%.

1H NMR (400 MHz, DMSO-d6) δ 7.38-7.21 (m, 4H), 7.03 (d, J=6.0 Hz, 1H),4.59 (d, J=13.9 Hz, 1H), 4.49 (d, J=13.9 Hz, 1H), 3.88 (d, J=12.9 Hz,1H), 3.75 (d, J=12.8 Hz, 1H), 2.64 (dd, J=13.0, 6.6 Hz, 1H), 2.63-2.52(m, 4H), 1.65-1.55 (m, 6H), 1.34 (tt, J=13.5, 8.1 Hz, 2H), 1.18 (dd,J=25.1, 12.9 Hz, 3H), 1.12-1.03 (m, 1H), 1.01 (d, J=6.2 Hz, 3H), 0.80(td, J=13.1, 6.4 Hz, 2H). m/z=339.2

B446:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-ethylmethanesulfonamide

1-(2-(aminomethyl)phenyl)-N-ethylmethanesulfonamide (0.5 mmol) and1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 28%.

1H NMR (400 MHz, DMSO-d6) δ 7.38-7.20 (m, 4H), 7.15 (t, J=5.6 Hz, 1H),4.58 (d, J=13.8 Hz, 1H), 4.48 (d, J=13.8 Hz, 1H), 3.88 (d, J=12.8 Hz,1H), 3.75 (d, J=12.9 Hz, 1H), 2.98-2.87 (m, 2H), 2.62 (q, J=6.4 Hz, 1H),2.54 (s, 1H), 1.65-1.54 (m, 7H), 1.34 (ddt, J=19.8, 13.5, 7.2 Hz, 2H),1.25-1.11 (m, 2H), 1.15-0.98 (m, 6H), 0.86-0.73 (m, 2H). m/z=353.2

B448:((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)glycine

((2-(aminomethyl)benzyl)sulfonyl)glycine (0.5 mmol),1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 29%.

1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=6.8 Hz, 1H), 7.45-7.33 (m, 3H),4.67 (t, J=9.8 Hz, 2H), 4.15 (d, J=13.3 Hz, 1H), 4.07 (d, J=13.5 Hz,1H), 3.06 (s, 1H), 1.64 (d, J=17.3 Hz, 4H), 1.56 (d, J=15.4 Hz, 2H),1.38-1.31 (m, 1H), 1.25 (s, 1H), 1.18 (d, J=6.4 Hz, 3H), 1.15 (s, 3H),0.86 (q, J=12.7, 12.0 Hz, 2H). m/z=383.2

B449:N-(cyclohexylcarbamoyl)-1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methanesulfonamide

1-(2-(aminomethyl)phenyl)-N-(cyclohexylcarbamoyl)methanesulfonamide (0.5mmol) and 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 37%.

1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 7.42 (d, J=7.2 Hz, 1H),7.37-7.25 (m, 3H), 5.90 (s, 1H), 4.51 (d, J=13.5 Hz, 1H), 4.30 (d,J=13.3 Hz, 1H), 4.18-4.06 (m, 2H), 3.34 (d, J=9.5 Hz, 2H), 1.73 (d,J=10.8 Hz, 2H), 1.69-1.57 (m, 8H), 1.53 (d, J=12.3 Hz, 1H), 1.38-1.29(m, 1H), 1.21 (dd, J=17.7, 5.4 Hz, 5H), 1.15 (s, 6H), 1.09 (t, J=11.1Hz, 2H), 0.91 (d, J=11.9 Hz, 1H), 0.85 (d, J=11.3 Hz, 1H). m/z=450.2

B450:1-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)-N-((4-methylcyclohexyl)carbamoyl)methanesulfonamide

1-(2-(aminomethyl)phenyl)-N-((4-methylcyclohexyl)carbamoyl)methanesulfonamide(0.5 mmol) and 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6ml MeOH, heated at 100° C. for 3 hours; then the mixture was cooled,NaBH₄ (0.5 mmol) was added and stirred for 5 hours. The mixture washeated for 2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18chromatographic phase were added, stirred for 2 hours, filtered. Theresidue was purified by HPLC. Yield: 28%.

1H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 0H), 7.36 (s, 1H), 7.32 (s, 1H),4.17 (s, 1H), 2.54 (s, 9H), 1.75 (s, 2H), 1.64 (s, 5H), 1.36 (s, 1H),1.27 (s, 3H), 1.13 (s, 3H), 0.91 (s, 2H), 0.85 (d, J=6.3 Hz, 2H).m/z=464.2

B451:2-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)ethane-1-sulfonamide

Step A:

1-cyclohexylpropan-2-amine (1 mmol),N-(tert-butyl)-2-(2-formylphenyl)ethane-1-sulfonamide (1 mmol) weredissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours; then themixture was cooled; NaBH₄ (1 mmol) was added and stirred for 4 hours.The mixture was heated for 2 hours at 60° C.; 3 ml of methanol and 0.4 gof C-18 chromatographic phase were added, stirred for 2 hours, filtered,evaporated. The residue was purified by HPLC. Yield: 54%.

Step B:

N-(tert-butyl)-2-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)ethane-1-sulfonamide(0.5 mmol) was dissolved in 2 ml MeOH; HCl (5 mmol) was added in themixture. The reaction stirred at 60° C. for 2 hours. The reactionmixture was concentrated under reduced pressure. The crude residue waspurified by HPLC. Yield: 29%.

1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 7.49 (d, J=7.0 Hz, 1H), 7.36(s, 3H), 6.94 (s, 2H), 4.15 (s, 2H), 3.10 (d, J=7.9 Hz, 2H), 1.67 (d,J=16.6 Hz, 6H), 1.38 (s, 2H), 1.30 (d, J=6.3 Hz, 2H), 1.20 (s, 3H), 0.96(d, J=12.3 Hz, 1H), 0.85 (d, J=12.1 Hz, 1H). m/z=339.2

B452:((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)glycylglycine

Step A:

Methyl ((2-(aminomethyl)benzyl)sulfonyl)glycylglycinate (1.5 mmol) and1-cyclohexylpropan-2-one (1.5 mmol) were dissolved in 0.8 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (1.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.4 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 34%.

Step B:

Methyl ((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)glycylglycinate (0.5 mmol) was dissolved in HCl (5 mmol). The reactionwas stirred at 50° C. overnight. The reaction was poured into water andextracted (2×) with dichloromethane. Reaction mixture was concentratedunder reduced pressure. The crude residue was purified by HPLC. Yield:26%.

1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.89 (s, 1H), 7.63 (d, J=6.9Hz, 1H), 7.55 (s, 1H), 7.42 (d, J=6.8 Hz, 1H), 7.37-7.32 (m, 2H),4.75-4.65 (m, 2H), 4.13 (d, J=13.5 Hz, 1H), 4.09 (d, J=13.6 Hz, 1H),3.15 (s, 1H), 2.05 (s, 1H), 1.60 (dd, J=21.8, 11.2 Hz, 7H), 1.39-1.31(m, 2H), 1.22 (d, J=6.5 Hz, 3H), 1.17 (s, 2H), 1.11 (dd, J=20.9, 10.8Hz, 2H), 0.84 (dq, J=35.4, 11.0 Hz, 2H). m/z=440.2

B453:(1S,3S)-3-(((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methyl)sulfonamido)cyclobutane-1-carboxylic acid

Step A:

Methyl(1s,3s)-3-(((2-(aminomethyl)phenyl)methyl)sulfonamido)cyclobutane-1-carboxylate(1.5 mmol) and 1-cyclohexylpropan-2-one (1.5 mmol) were dissolved in 0.8ml MeOH, heated at 100° C. for 3 hours; then the mixture was cooled,NaBH₄ (1.5 mmol) was added and stirred for 5 hours. The mixture washeated for 2 hours at 60° C.; 3 ml of methanol and 0.4 g of C-18chromatographic phase were added, stirred for 2 hours, filtered. Theresidue was purified by HPLC. Yield: 41%.

Step B:

Methyl(1s,3s)-3-(((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methyl)sulfonamido)cyclobutane-1-carboxylate (0.5 mmol) was dissolved in HCl (5mmol). The reaction was stirred at 50° C. overnight. The reaction waspoured into water and extracted (2×) with dichloromethane. Reactionmixture was concentrated under reduced pressure. The crude residue waspurified by HPLC. Yield: 34%.

1H NMR (500 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.35 (s, 1H), 7.27 (s, 4H),4.54 (s, 1H), 4.40 (d, J=14.2 Hz, 1H), 4.32 (s, 2H), 3.93-3.87 (m, 1H),3.77 (s, 1H), 2.65 (s, 1H), 2.56 (s, 1H), 2.34 (s, 3H), 2.06 (s, 2H),1.59 (s, 6H), 1.34 (s, 2H), 1.16 (s, 3H), 1.08 (s, 2H), 1.02 (s, 4H),0.80 (s, 3H), 0.56 (s, 1H). m/z=423.2

B454:((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)-L-alanine

Step A:

Methyl ((2-(aminomethyl)benzyl)sulfonyl)-L-alaninate (1.5 mmol) and1-cyclohexylpropan-2-one (1.5 mmol) were dissolved in 0.8 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (1.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.4 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 34%.

Step B:

Methyl((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)-L-alaninate(0.5 mmol) was dissolved in HCl (5 mmol). The reaction was stirred at50° C. overnight. The reaction was poured into water and extracted (2×)with dichloromethane. Reaction mixture was concentrated under reducedpressure. The crude residue was purified by HPLC. Yield: 27%.

1H NMR (400 MHz, Methanol-d4) δ 7.52 (d, J=7.1 Hz, 2H), 7.45 (d, J=4.7Hz, 2H), 4.73 (d, J=14.2 Hz, 1H), 4.51 (dd, J=14.1, 8.9 Hz, 1H), 4.35(dd, J=17.6, 10.1 Hz, 2H), 3.82 (s, 1H), 3.48 (s, 1H), 3.29 (s, 2H),1.75 (s, 0H), 1.69 (s, 5H), 1.43 (s, 2H), 1.38 (d, J=6.9 Hz, 5H), 1.30(d, J=14.6 Hz, 1H), 1.21 (dd, J=20.3, 11.3 Hz, 1H), 1.06-0.89 (m, 2H).m/z=397.2

B455:((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)-D-alanine

Step A:

Methyl ((2-(aminomethyl)benzyl)sulfonyl)-D-alaninate (1.5 mmol) and1-cyclohexylpropan-2-one (1.5 mmol) were dissolved in 0.8 ml MeOH,heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄ (1.5mmol) was added and stirred for 5 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.4 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 39%.

Step B:

Methyl((2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)sulfonyl)-D-alaninate(0.5 mmol) was dissolved in HCl (5 mmol). The reaction stirred at 50° C.overnight. The reaction was poured into water and extracted (2×) withdichloromethane. Reaction mixture was concentrated under reducedpressure. The crude residue was purified by HPLC. Yield: 24%. m/z=397.2

B456: (1S,3S)-3-(((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methyl)sulfonamido)cyclobutane-1-carboxylic acid

Synthetic Procedure 1 Step A:

Methyl(1r,3r)-3-(((2-(aminomethyl)phenyl)methyl)sulfonamido)cyclobutane-1-carboxylate(1.5 mmol) and 1-cyclohexylpropan-2-one (1.5 mmol) were dissolved in 0.8ml MeOH, heated at 100° C. for 3 hours; then the mixture was cooled,NaBH₄ (1.5 mmol) was added and stirred for 5 hours. The mixture washeated for 2 hours at 60° C.; 3 ml of methanol and 0.4 g of C-18chromatographic phase were added, stirred for 2 hours, filtered. Theresidue was purified by HPLC. Yield: 44%.

Step B:

Methyl(1r,3r)-3-(((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methyl)sulfonamido) cyclobutane-1-carboxylate (0.5 mmol) was dissolved in HCl(5 mmol). The reaction was stirred at 50° C. overnight. The reaction waspoured into water and extracted (2×) with dichloromethane. Reactionmixture was concentrated under reduced pressure. The crude residue waspurified by HPLC. Yield: 31%.

Synthetic Procedure 2 Step A:

Methyl (1r,3r)-3-((2-((2-(aminomethyl)phenoxy)methyl)phenyl)sulfonamido)cyclobutane-1-carboxylate (1 mmol), and 1-cyclohexylpropan-2-one (1mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours; thenthe mixture was cooled, NaBH₄ (1 mmol) was added and stirred for 4hours. The mixture was heated for 2 hours at 60° C.; 3 ml of methanoland 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours,filtered, evaporated. The residue was purified by HPLC. Yield: 54%.

Step B:

To a solution of methyl(1r,3r)-3-((2-((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenoxy)methyl)phenyl)sulfonamido)cyclobutane-1-carboxylate(0.5 mmol) in EtOH/H₂O (5.0/2.5 ml) was added NaOH (1.5 mmol). Thereaction stirred at room temperature overnight. To the reaction wasadded CH₃COOH (1.5 mmol) and it was extracted (2×) with dichloromethane.The organic layers were dried over magnesium sulfate, filtered andconcentrated. The crude residue was purified by HPLC. Yield: 38%.

1H NMR (500 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.33 (d, J=7.3 Hz, 1H), 7.25(q, J=8.2, 7.5 Hz, 3H), 4.53 (d, J=13.8 Hz, 1H), 4.39 (d, J=13.8 Hz,1H), 4.32 (s, 1H), 3.87 (d, J=12.3 Hz, 2H), 3.72 (d, J=12.9 Hz, 1H),2.78 (t, J=9.8 Hz, 1H), 2.67-2.60 (m, 1H), 2.38-2.30 (m, 2H), 2.16 (q,J=10.2 Hz, 2H), 1.61 (s, 2H), 1.56 (d, J=14.8 Hz, 3H), 1.37-1.26 (m,2H), 1.16 (d, J=12.2 Hz, 1H), 1.14-0.99 (m, 3H), 1.00 (s, 1H), 0.81 (q,J=12.1 Hz, 2H). m/z=423.2

B457:(3-(((2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)methyl)sulfonamido)phenyl)boronic acid

(4-(((2-(aminomethyl)phenyl)methyl)sulfonamido)phenyl)boronic acid (0.5mmol) and 1-cyclohexylpropan-2-one (0.5 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 3 hours; then the mixture was cooled, NaBH₄(0.5 mmol) was added and stirred for 5 hours. The mixture was heated for2 hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered. The residue waspurified by HPLC. Yield: 24%.

1H NMR (500 MHz, Methanol-d4) δ 7.47 (d, J=6.7 Hz, 1H), 7.47-7.34 (m,5H), 7.24 (t, J=7.6 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 4.61 (d, J=14.4 Hz,1H), 4.57 (d, J=14.4 Hz, 1H), 4.11 (d, J=13.3 Hz, 1H), 4.04 (d, J=13.3Hz, 1H), 3.15 (s, 1H), 2.66 (s, 1H), 1.71 (dd, J=27.8, 12.8 Hz, 6H),1.56 (ddd, J=13.2, 8.5, 4.4 Hz, 1H), 1.39-1.15 (m, 6H), 1.00 (dd,J=13.4, 10.4 Hz, 1H), 0.92 (td, J=13.5, 12.3, 6.7 Hz, 1H). m/z=445.2

B458: 1-cyclohexyl-N-(2-(2-isopropylbenzyl)oxy)benzyl)propan-2-amine

(2-((2-isopropylbenzyl)oxy)phenyl)methanamine (0.5 mmol) and1-cyclohexylpropan-2-one (0.55 mmol) were dissolved in 0.6 ml MeOH,heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (0.5mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, evaporated. The residuewas purified by HPLC. Yield: 39%.

1H NMR (400 MHz, Chloroform-d) δ 9.43 (s, 1H), 9.10 (s, 1H), 7.74 (d,J=7.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.36-7.26 (m, 2H),7.25 (d, J=8.4 Hz, 1H), 7.21-7.13 (m, 1H), 7.00-6.88 (m, 2H), 5.16 (s,2H), 3.97 (d, J=13.2 Hz, 1H), 3.91 (d, J=13.9 Hz, 1H), 3.16 (hept, J=6.8Hz, 1H), 2.93 (s, 1H), 1.58 (d, J=5.8 Hz, 2H), 1.40 (d, J=10.4 Hz, 1H),1.37 (d, J=11.2 Hz, 2H), 1.23 (d, J=6.8 Hz, 6H), 1.17 (d, J=6.5 Hz, 4H),1.04 (s, 1H), 1.00 (s, 1H), 0.76-0.63 (m, 1H), 0.60 (d, J=11.9 Hz, 1H).m/z=380.2

13C NMR (126 MHz, Chloroform-d) δ 157.23, 147.47, 132.71, 132.48,130.65, 129.97, 128.94, 125.95, 125.48, 121.08, 119.45, 111.62, 68.21,51.03, 41.87, 39.77, 33.94, 33.81, 31.54, 28.83, 26.29, 26.10, 25.88,24.11, 24.03, 16.29.

B459: 1-cyclohexyl-N-(2-((3-methoxybenzyl)oxy)benzyl)propan-2-amine

(2-((3-methoxybenzyl)oxy)phenyl)methanamine (1 mmol),1-cyclohexylpropan-2-one (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100° C. for 2 hours; then mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C.; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated. The residue was purified byHPLC. Yield: 44%.

1H NMR (500 MHz, Chloroform-d) δ 9.48 (s, 1H), 9.12 (s, 1H), 7.76-7.70(m, 1H), 7.32-7.23 (m, 1H), 7.05 (t, J=5.8 Hz, 2H), 6.97-6.90 (m, 2H),6.87 (dd, J=8.5, 2.6 Hz, 1H), 5.11 (d, J=2.2 Hz, 2H), 3.99 (p, J=7.4,6.6 Hz, 2H), 3.82 (s, 3H), 3.00 (tt, J=10.2, 5.1 Hz, 1H), 1.68 (ddd,J=13.4, 9.5, 4.0 Hz, 1H), 1.63-1.56 (m, 3H), 1.50-1.39 (m, 3H), 1.26 (d,J=6.5 Hz, 3H), 1.21 (s, 2H), 1.17 (s, 1H), 1.09 (p, J=12.6, 12.0 Hz,2H), 0.76 (qd, J=12.3, 3.2 Hz, 1H), 0.66 (tt, J=12.1, 6.0 Hz, 1H).m/z=368.2

B460: 1-cyclohexyl-N-(2-((4-methylbenzyl)oxy)benzyl)propan-2-amine

(2-((4-methylbenzyl)oxy)phenyl)methanamine (1 mmol) and1-cyclohexylpropan-2-one (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C.; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated. The residue was purified byHPLC. Yield: 38%.

1H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 9.04 (s, 1H), 7.69 (d,J=7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.24 (dd, J=9.9, 5.8 Hz, 1H),7.15 (d, J=7.6 Hz, 2H), 6.92 (p, J=8.5, 7.4 Hz, 2H), 5.05 (s, 2H), 3.95(q, J=4.9 Hz, 2H), 2.94 (dt, J=11.0, 5.7 Hz, 1H), 2.32 (s, 3H), 1.58(dd, J=14.4, 8.8 Hz, 4H), 1.39 (tt, J=13.7, 5.2 Hz, 3H), 1.21 (d, J=6.5Hz, 3H), 1.10 (dq, J=34.3, 9.4, 8.8 Hz, 4H), 0.71 (t, J=11.7 Hz, 1H),0.62 (t, J=11.8 Hz, 1H). m/z=352.4

B461: 1-cyclohexyl-N-(2-((3-methylbenzyl)oxy)benzyl)propan-2-amine

(2-((3-methylbenzyl)oxy)phenyl)methanamine (1 mmol) and1-cyclohexylpropan-2-one (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C.; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated. The residue was purified byHPLC. Yield: 32%.

1H NMR (500 MHz, Chloroform-d) δ 9.50 (s, 1H), 9.18 (s, 1H), 7.75 (dd,J=7.5, 1.7 Hz, 1H), 7.31-7.21 (m, 4H), 7.16-7.11 (m, 1H), 6.93 (t, J=8.1Hz, 2H), 5.09 (s, 2H), 4.00 (q, J=4.5 Hz, 2H), 2.98 (dt, J=11.1, 5.5 Hz,1H), 2.36 (s, 3H), 1.67 (ddd, J=13.5, 9.6, 4.0 Hz, 1H), 1.59 (dd,J=12.0, 6.5 Hz, 2H), 1.49-1.37 (m, 3H), 1.25 (d, J=6.5 Hz, 3H), 1.19 (s,2H), 1.19-1.00 (m, 2H), 0.74 (qd, J=12.3, 3.3 Hz, 1H), 0.64 (qd, J=12.0,3.0 Hz, 1H), −1.15 (s, 1H). m/z=352.4

B462: 1-cyclohexyl-N-(2-((2-cyclopropylbenzyl)oxy)benzyl)propan-2-amine

(2-((2-cyclopropylbenzyl)oxy)phenyl)methanamine (1 mmol) and1-cyclohexylpropan-2-one (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C.; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated. The residue was purified byHPLC. Yield: 37%.

1H NMR (500 MHz, Chloroform-d) δ 17.10 (s, 1H), 9.50 (s, 1H), 9.17 (s,1H), 7.78 (d, J=7.4 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 7.27 (dt, J=15.5,7.7 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H), 7.01 (dd, J=16.7, 8.0 Hz, 2H), 6.95(t, J=7.5 Hz, 1H), 5.32 (s, 2H), 4.04 (d, J=5.9 Hz, 1H), 4.01 (d, J=5.8Hz, 1H), 2.98 (dt, J=11.6, 5.6 Hz, 1H), 1.98 (tt, J=8.5, 5.3 Hz, 1H),1.65 (ddd, J=13.6, 9.6, 3.9 Hz, 1H), 1.57 (d, J=8.5 Hz, 3H), 1.47-1.37(m, 3H), 1.24-1.13 (m, 4H), 1.07 (dt, J=25.2, 13.9 Hz, 2H), 0.94 (dq,J=6.2, 3.8 Hz, 2H), 0.78-0.67 (m, 3H), 0.70-0.57 (m, 1H). m/z=378.2

B463: 1-cyclohexyl-N-(2-((2-phenoxybenzyl)oxy)benzyl)propan-2-amine

(2-((2-phenoxybenzyl)oxy)phenyl)methanamine (1 mmol) and1-cyclohexylpropan-2-one (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C.; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added,stirred for 2 hours, filtered, evaporated. The residue was purified byHPLC. Yield: 39%.

1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J=7.5 Hz, 1H), 7.39 (d, J=7.7 Hz,2H), 7.34 (d, J=13.0 Hz, 2H), 7.30-7.17 (m, 2H), 7.13 (t, J=7.4 Hz, 1H),7.08 (d, J=8.2 Hz, 1H), 6.95 (dd, J=22.4, 8.0 Hz, 4H), 5.15 (s, 2H),3.81 (s, 2H), 2.79 (s, 1H), 1.56 (s, 3H), 1.49 (d, J=15.3 Hz, 2H), 1.34(s, 1H), 1.24 (s, 1H), 1.09 (s, 5H), 1.01 (s, 2H), 0.74 (s, 2H).m/z=430.2

B464: 2-(2-(3-methylcyclohexyl)ethyl)-1,4-dihydroisoquinolin-3 (2H)-one

2-(3-methylcyclohexyl)ethan-1-amine (0.5 mmol) and methyl2-(2-(chloromethyl)phenyl)acetate (0.5 mmol) were mixed in 5 ml of DMF;DIPEA (0.75 mmol) was added. The mixture was heated at 80° C. for 5 h,cooled; solvent was removed by evaporation and residue was purified byHPLC. Yield: 32%.

1H NMR (400 MHz, Chloroform-d) δ 7.26-7.10 (m, 4H), 4.42 (s, 2H), 3.57(s, 2H), 3.50 (p, J=7.4, 6.4 Hz, 2H), 3.44 (s, 1H), 1.73 (dq, J=11.1,4.0 Hz, 1H), 1.72-1.58 (m, 1H), 1.62-1.37 (m, 4H), 1.37-1.17 (m, 1H),1.09 (td, J=10.2, 7.9, 4.7 Hz, 1H), 0.85 (t, J=6.5 Hz, 3H), 0.84-0.71(m, 1H). m/z=272.2

B465:N-(2-((2-fluorobenzyl)oxy)benzyl)-1-(4-methylcyclohexyl)propan-2-amine

1-(4-methylcyclohexyl)propan-2-amine (1 mmol) and2-((2-fluorobenzyl)oxy)benzaldehyde (1 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(1 mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C.; 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, the solvent wasevaporated. The residue was purified by HPLC. Yield: 57%.

1H NMR (400 MHz, DMSO-d6) δ 7.61-7.53 (m, 1H), 7.41 (tdd, J=7.6, 5.4,1.8 Hz, 1H), 7.32-7.22 (m, 2H), 7.25-7.16 (m, 2H), 7.09 (d, J=8.1 Hz,1H), 6.90 (t, J=7.3 Hz, 1H), 5.15 (s, 2H), 3.76-3.67 (m, 1H), 3.60 (d,J=13.7 Hz, 1H), 2.60-2.47 (m, 1H), 1.54 (dd, J=13.2, 8.3 Hz, 3H),1.50-1.43 (m, 1H), 1.22-1.09 (m, 3H), 1.04-0.90 (m, 1H), 0.90 (d, J=6.1Hz, 2H), 0.82 (dd, J=13.9, 6.7 Hz, 2H), 0.78-0.68 (m, 3H). m/z=370.2

B466:2-amino-3-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)phenyl)propanoicacid

Step A:

diethyl 2-acetamido-2-(2-(aminomethyl)benzyl)malonate (1 mmol) and1-cyclohexylpropan-2-one (1 mmol) were dissolved in 0.6 ml MeOH, heatedat 100° C. for 2 hours; then the mixture was cooled, NaBH₄ (1 mmol) wasadded and stirred for 4 hours. The mixture was heated for 2 hours at 60°C. Water (5 ml) were added, the organic layer was extracted with EtOAc(3*10 ml) and concentrated in vacuo. The residue was purified by HPLC.Yield: 57%.

Step B:

Diethyl2-acetamido-2-(2-(((1-cyclohexylpropan-2-yl)amino)methyl)benzyl)malonate(0.05 mmol) was dissolved in 0.5 ml MeOH; 0.1 ml HCl was added. Themixture was refluxed for 1 hour. The precipitate was filtered and waspurified by LC. Yield: 39%.

1H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J=7.5 Hz, 1H), 7.24 (d, J=8.0Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.71 (s, 4H), 4.00 (t, J=11.5 Hz, 1H),3.79 (d, J=12.1 Hz, 1H), 3.55 (s, 1H), 3.20 (t, J=9.9 Hz, 1H), 3.00 (s,2H), 1.66 (q, J=11.7, 10.9 Hz, 6H), 1.40-1.34 (m, 1H), 1.32-1.27 (m,2H), 1.27-1.19 (m, 4H), 1.14 (dt, J=22.2, 11.8 Hz, 2H), 0.89 (dp,J=40.3, 11.5, 10.8 Hz, 2H). m/z=319.2

B467:(2S)-2-amino-3-(2-(((2-cyclohexylpropyl)amino)methyl)phenyl)propanoicacid

Step A:

diethyl 2-acetamido-2-(2-(aminomethyl)benzyl)malonate (5 mmol) and2-cyclohexylpropanal (5 mmol) were dissolved in 1.5 ml MeOH, heated at100° C. for 2 hours; then the mixture was cooled, NaBH₄ (5 mmol) wasadded and stirred for 1 hours at r.t. Thereafter, water (15 ml) wasadded, the organic layer was extracted with EtOAc (3×15 ml), andconcentrated in vacuo. The residue was purified using HPLC. Yield: 54%.

Step B:

To a solution of diethyl2-acetamido-2-(2-(((2-cyclohexylpropyl)amino)methyl)benzyl)malonate (2.5mmol) in ethanol (10 ml) was added potassium hydroxide (2.5 mmol). Thereaction was allowed to stir at reflux for 8 h and was thenconcentrated. The residue was dissolved in water and extracted withEtOAc. The aqueous layer was cooled to 0° C., carefully acidified to pH2-3 using HCl, and extracted with EtOAc. The combined organics weredried over sodium sulfate, filtered, concentrated and purified by chiralchromatographic purification. Yield: 41%.

Step C:

(2S)-2-acetamido-3-(2-(((2-cyclohexylpropyl)amino)methyl)phenyl)propanoicacid (1 mmol) was dissolved in 0.5 ml AcOH; 0.2 ml HCl was added and wasstirred for 2 hours. The precipitate was filtered and was purified usingLC. Yield: 51%.

1H NMR (500 MHz, DMSO-d6) δ 7.04-6.89 (m, 3H), 6.90 (s, 1H), 4.28 (d,J=8.2 Hz, 8H), 3.83 (td, J=15.8, 15.4, 12.0 Hz, 2H), 3.65 (dd, J=9.0,6.2 Hz, 1H), 2.96-2.88 (m, 1H), 2.78 (d, J=14.3 Hz, 1H), 2.66 (s, 1H),2.46 (d, J=9.6 Hz, 1H), 1.28 (s, 1H), 1.21 (s, 2H), 1.19 (d, J=3.8 Hz,1H), 1.12 (d, J=12.8 Hz, 1H), 1.05 (d, J=12.3 Hz, 2H), 0.74-0.65 (m,1H), 0.63-0.49 (m, 1H), 0.47 (s, 2H), 0.45 (dd, J=7.1, 2.8 Hz, 2H).m/z=317.1

B468: 1-cyclohexyl-N-(2-(2-fluorophenethyl)benzyl)propan-2-amine

1-cyclohexylpropan-2-one (1 mmol) and(2-(2-fluorophenethyl)phenyl)methanamine (1 mmol) were dissolved in 0.6ml MeOH, heated at 100° C. for 2 hours; then the mixture was cooled,NaBH₄ (1 mmol) was added and stirred for 4 hours. The mixture was heatedfor 2 hours at 60° C., 3 ml of methanol and 0.2 g of C-18chromatographic phase were added, stirred for 2 hours, filtered, thesolvent was evaporated. The residue was purified using HPLC. Yield: 31%.1H NMR (400 MHz, Chloroform-d) δ 7.30 (d, J=4.4 Hz, 1H), 7.20-7.10 (m,5H), 7.02 (q, J=8.4, 7.8 Hz, 2H), 3.80 (d, J=12.5 Hz, 1H), 3.67 (d,J=12.5 Hz, 1H), 2.99-2.90 (m, 4H), 2.77 (q, J=6.7 Hz, 1H), 1.62 (d,J=10.3 Hz, 5H), 1.39-1.30 (m, 1H), 1.10 (dd, J=23.7, 6.7 Hz, 5H), 0.84(d, J=11.7 Hz, 2H). m/z=354.2

B469:N-(2-((2-fluorobenzyl)oxy)benzyl)-1-(4-(trifluoromethyl)cyclohexyl)propan-2-amine

1-(4-(trifluoromethyl)cyclohexyl)propan-2-one (1 mmol) and(2-((2-fluorobenzyl)oxy)phenyl)methanamine (1 mmol) were dissolved in0.6 ml MeOH, heated at 100° C. for 2 hours; then the mixture was cooled,NaBH₄ (1 mmol) was added and stirred for 4 hours. The mixture was heatedfor 2 hours at 60° C., 3 ml of methanol and 0.2 g of C-18chromatographic phase were added, stirred for 2 hours, filtered, thesolvent was evaporated. The residue was purified using HPLC. Yield: 28%.

1H NMR (400 MHz, Chloroform-d) δ 7.48 (s, 1H), 7.31 (d, J=7.1 Hz, 1H),7.22 (t, J=9.4 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H),6.99-6.88 (m, 2H), 5.13 (s, 2H), 3.86 (dd, J=13.1, 8.6 Hz, 1H), 3.73(dd, J=13.0, 8.8 Hz, 1H), 2.67-2.53 (m, 1H), 1.82 (t, J=13.7 Hz, 1H),1.51 (s, 1H), 1.41 (s, 1H), 1.34 (ddd, J=25.5, 12.2, 6.1 Hz, 1H),1.27-1.07 (m, 2H), 1.01 (td, J=6.6, 2.5 Hz, 3H), 0.84-0.73 (m, 1H).m/z=424.2

B470:1-(4-ethylcyclohexyl)-N-(2-((2-fluorobenzyl)oxy)benzyl)propan-2-amine

1-(4-ethylcyclohexyl)propan-2-amine (1 mmol) and2-((2-fluorobenzyl)oxy)benzaldehyde (1 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(1 mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, the solvent wasevaporated. The residue was purified using HPLC. Yield: 38%.

1H NMR (400 MHz, Chloroform-d) δ 7.50 (t, J=7.5 Hz, 1H), 7.35-7.23 (m,1H), 7.22 (d, J=7.6 Hz, 1H), 7.21-7.11 (m, 1H), 7.07 (dd, J=10.2, 8.1Hz, 1H), 6.97-6.91 (m, 1H), 6.91 (d, J=7.3 Hz, 1H), 5.14 (s, 2H), 3.87(dd, J=13.1, 6.2 Hz, 1H), 3.74 (dd, J=13.0, 4.3 Hz, 1H), 2.70-2.57 (m,1H), 1.73 (s, 1H), 1.63 (s, 2H), 1.44-1.25 (m, 1H), 1.23 (d, J=6.5 Hz,1H), 1.17 (dd, J=15.3, 8.6 Hz, 1H), 1.12-0.98 (m, 2H), 0.99 (s, 1H),0.87-0.67 (m, 4H). m/z=384.2.

B471:N-(2-((2-fluorobenzyl)oxy)benzyl)-1-(4-isopropylcyclohexyl)propan-2-amine

1-(4-isopropylcyclohexyl)propan-2-amine (1 mmol) and2-((2-fluorobenzyl)oxy)benzaldehyde (1 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then mixture was cooled, NaBH₄ (1mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, the solvent wasevaporated. The residue was purified using HPLC. Yield: 41%.

1H NMR (400 MHz, Chloroform-d) δ 7.50 (t, J=7.7 Hz, 1H), 7.30 (d, J=7.0Hz, 1H), 7.18 (dt, J=26.1, 6.7 Hz, 2H), 7.07 (t, J=9.2 Hz, 1H), 6.93(dd, J=12.3, 7.6 Hz, 2H), 5.15 (s, 2H), 3.88 (d, J=13.1 Hz, 1H), 3.74(d, J=13.1 Hz, 1H), 2.65 (d, J=6.4 Hz, 1H), 1.58 (dt, J=27.6, 12.6 Hz,4H), 1.30 (dq, J=13.2, 6.6 Hz, 1H), 1.08 (dd, J=12.8, 6.3 Hz, 1H), 1.00(d, J=6.2 Hz, 3H), 0.80 (d, J=6.9 Hz, 7H), 0.74 (d, J=11.6 Hz, 1H).m/z=398.2

B472:1-(4-cyclopropylcyclohexyl)-N-(2-((2-fluorobenzyl)oxy)benzyl)propan-2-amine

1-(4-cyclopropylcyclohexyl)propan-2-amine (1 mmol) and2-((2-fluorobenzyl)oxy)benzaldehyde (1 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then mixture was cooled, NaBH₄ (1mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, the solvent wasevaporated. The residue was purified using HPLC. Yield: 32%.

1H NMR (400 MHz, Chloroform-d) δ 7.50 (t, J=7.7 Hz, 2H), 7.30 (d, J=7.0Hz, 1H), 7.26-7.03 (m, 6H), 6.97-6.88 (m, 3H), 5.14 (s, 3H), 3.88 (d,J=13.4 Hz, 2H), 3.75 (dd, J=13.2, 8.5 Hz, 2H), 2.65 (s, 2H), 1.70 (s,4H), 1.61 (d, J=13.1 Hz, 1H), 1.40 (s, 7H), 1.31-1.16 (m, 1H), 1.20 (s,6H), 1.13-0.98 (m, 5H), 0.94 (d, J=12.2 Hz, 1H), 0.90 (s, 1H), 0.76-0.66(m, 2H), 0.53 (s, 1H), 0.33 (dd, J=15.5, 7.8 Hz, 5H). m/z=396.2

B473:1-(4,4-difluorocyclohexyl)-N-(2-((2-fluorobenzyl)oxy)benzyl)propan-2-amine

1-(4,4-difluorocyclohexyl)propan-2-amine (1 mmol) and2-((2-fluorobenzyl)oxy)benzaldehyde (1 mmol) were dissolved in 0.6 mlMeOH, heated at 100° C. for 2 hours; then the mixture was cooled, NaBH₄(1 mmol) was added and stirred for 4 hours. The mixture was heated for 2hours at 60° C., 3 ml of methanol and 0.2 g of C-18 chromatographicphase were added, stirred for 2 hours, filtered, the solvent wasevaporated. The residue was purified using HPLC. Yield: 39%.

1H NMR (400 MHz, Chloroform-d) δ 7.48 (dd, J=8.4, 6.6 Hz, 1H), 7.32 (d,J=7.2 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.23 (s, 1H), 7.22-7.13 (m, 1H),7.10 (dd, J=18.8, 9.4 Hz, 1H), 6.99-6.89 (m, 2H), 5.13 (s, 2H), 3.87 (d,J=13.1 Hz, 1H), 3.73 (d, J=13.1 Hz, 1H), 2.62 (dt, J=11.7, 5.7 Hz, 1H),1.62 (d, J=12.5 Hz, 2H), 1.58-1.46 (m, 2H), 1.36 (q, J=6.2, 5.6 Hz, 1H),1.32 (s, 2H), 1.18-1.07 (m, 3H), 1.02 (d, J=6.2 Hz, 3H). m/z=392.3

B1: N-benzyl-2-(cyclohex-1-en-1-yl)ethan-1-amine

2-(cyclohex-1-en-1-yl)ethan-1-amine (0.5 mmol) and benzaldehyde (0.55mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours; thenthe mixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for 4hours. The mixture was heated for 2 hours at 60° C.; 3 ml of methanoland 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours,filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue waspurified by HPLC. Yield: 41%.

1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 2H), 7.61 (d, J=7.6 Hz, 2H), 7.39(d, J=6.4 Hz, 3H), 5.46 (s, 1H), 4.07 (t, J=5.6 Hz, 2H), 3.11 (s, 2H),2.88 (d, J=9.0 Hz, 2H), 2.36 (t, J=8.3 Hz, 2H), 1.98 (s, 2H), 1.90 (d,J=7.4 Hz, 2H), 1.60 (q, J=5.7 Hz, 2H), 1.55 (q, J=5.9 Hz, 2H). m/z=216.2

B10: 2-(cyclohex-1-en-1-yl)-N-(4-methylbenzyl)ethan-1-amine

2-(cyclohex-1-en-1-yl)ethan-1-amine (0.5 mmol) and 4-methylbenzaldehyde(0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours;then the mixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for4 hours. The mixture was heated for 2 hours at 60° C.; 3 ml of methanoland 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours,filtered, evaporated. The residue was purified by HPLC. Yield: 39%.

1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.22(d, J=7.7 Hz, 1H), 5.43 (s, 0H), 4.06 (t, J=5.6 Hz, 1H), 2.88 (dq,J=11.3, 6.0 Hz, 1H), 2.31 (s, 3H), 1.94 (s, 1H), 1.85 (d, J=6.7 Hz, 1H),1.59-1.53 (m, 1H), 1.53-1.43 (m, 1H). m/z=230.4

B11: 2-(cyclohex-1-en-1-yl)-N-(3-methylbenzyl)ethan-1-amine

2-(cyclohex-1-en-1-yl)ethan-1-amine (0.5 mmol) and 3-methylbenzaldehyde(0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours;then the mixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for4 hours. The mixture was heated for 2 hours at 60° C.; 3 ml of methanoland 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours,filtered, evaporated and the residue was purified by HPLC. Yield: 41%.

1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H), 7.36-7.26 (m, 3H), 7.21 (d,J=6.5 Hz, 1H), 5.44 (s, 1H), 4.05 (s, 2H), 2.94-2.86 (m, 2H), 2.30 (d,J=18.1 Hz, 6H), 1.94 (s, 2H), 1.87 (s, 2H), 1.61-1.53 (m, 2H), 1.49 (dd,J=6.7, 4.5 Hz, 1H). m/z=230.2

B13: 2-(cyclohex-1-en-1-yl)-N-(2-methylbenzyl)ethan-1-amine

2-(cyclohex-1-en-1-yl)ethan-1-amine (0.5 mmol) and 2-methylbenzaldehyde(0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C. for 2 hours;then the mixture was cooled, NaBH₄ (0.5 mmol) was added and stirred for4 hours. The mixture was heated for 2 hours at 60° C.; 3 ml of methanoland 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours,filtered, evaporated. The residue was purified by HPLC. Yield: 43%.

1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 2H), 7.57-7.51 (m, 1H), 7.34-7.21(m, 3H), 5.47 (s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.03 (dq, J=11.3, 5.9 Hz,2H), 2.56-2.47 (m, 2H), 2.37 (d, J=10.0 Hz, 5H), 1.96 (s, 2H), 1.91 (s,1H), 1.58 (dd, J=10.7, 6.0 Hz, 2H), 1.52 (p, J=5.9 Hz, 2H). m/z=230.2

Example 14: Gram Negative (E. coli and A. baumannii) MIC protocol

Overnight bacterial cultures were grown in LB with no added antibioticsat 37° C. with shaking. A 1:1000 dilution of these cultures into LB wasexposed to concentration gradients of compounds in 96-well plates (100μL per well assay volume). Resulting plates were incubated at 37° C. for24 h without shaking, and OD600 was measured at the end of theincubation. MICs were determined as the lowest concentrations at whichOD600 remained at baseline.

Antibacterial activity of the compounds of the invention is shown inTable 3.

Example 15: Tuberculosis Assay

A luminescence assay was carried out via the following steps. The strainused in the luminescence assay was H37RvMA with the LuxCDABE operonintegrated at the L5 site on a Kanamycin marked plasmid(pMV306hsp+LuxG13):

-   -   1. Inoculate −80 stock into 7H9 OADC+Kan (25 ug/mL)    -   2. When bacteria reach mid-log phase, passage cells in 7H9        OADC+Kan25    -   3. When cells reach mid log phase dilute to OD=0.05 in 7H9 OADC    -   4. Add 100 uL of cells to each well of the plate    -   5. Seal the plate with an optical film and read luminescence        using the following protocol:        -   a. Plate reader: Biotek Synergy H1        -   b. Double orbital shaking (10 s); frequency: 282 cpm (3 mm)        -   c. Luminescence endpoint parameters: is integration time,            gain 200, read height 1 mm    -   6. Remove optical film, seal with a breathable film, and        incubate shaking at 37 C    -   7. Read luminescence at day 0, 1, 4, and 7

An Alamar Blue/Resazurin assay was carried out via the following steps.The strain used in the Alamar Blue/Resazurin assay was H37RvMA:

-   -   1. Inoculate −80 stocks into 7H9 OADC    -   2. When cells reach mid-log phase passage in 7H9 OADC    -   3. When cells reach mid log phase, dilute to OD=0.006    -   4. Add 100 uL of cells (diluted to OD=0.006) to the plate        (making final OD in plate 0.003)    -   5. Seal the plate with breathable film, place in a ziplock, and        put the plate in a box        -   a. Incubate shaking at 37° C. for 4 days    -   6. After incubation, add 20 uL of Resazurin/alamar blue (0.02%)        to every well (not including water wells    -   7. Re-seal the plates and incubate at 37° C., check the plates        after 24 and 48 hours        -   a. Purple=no growth, pink=growth        -   b. MIC recorded as the well with the lowest concentration of            drug that there is killing (purple color).

Example 16: Antibacterial and Anti-Tuberculosis Activities

TABLE 3 Antimicrobial Activity MIC MIC WT E. coli WT E. coli delta- MICH37Rv LB TolC LB A. baumannii MTB Media Media LB Media Activity FRS-ID(μM) (μM) (μM) (μM) B1

   60    46   150 >150 B2

>150 >150 >150 >150 B3

>150 >150 >150 >150 B4

>150 >150 >150 >150 B5

>150 >150 >150 >150 B6

>150 >150 >150 >150 B7

>150 >150 >150 >150 B8

>150 >150 >150 >150 B9

>150 >150 >150 >150 B10

>150 >150 >150 >150 B11

>150 >150 >150 >150 B12

>150 >150 >150 >150 B13

   90    55   150 >150 B14

>150 >150 >150 >150 B15

>150 >150 >150 >150 B16

>150 >150 >150 >150 B17

>150 >150 >150 >150 B18

>150 >150 >150 >150 B19

>150 >150 >150   150 B20

>150 >150 >150 >150 B21

>150 >150 >150 >150 B22

>150 >150 >150 >150 B23

>150 >150 >150 >150 B24

>150 >150 >150 >150 B25

>150 >150 >150 >150 B26

>150 >150 >150 >150 B27

>150 >150 >150    91 B28

>150 >150 >150 >150 B29

>150 >150 >150 >150 B30

>150 >150 >150 >150 B31

>150 >150 >150 >150 B32

>150 >150 >150 >150 B33

>150 >150 >150 >150 B34

>150 >150 >150 >150 B35

>150 >150 >150 >150 B36

>150 >150 >150 >150 B37

>150 >150 >150   150 B38

   91    90   150 >150 B39

>150 >150 >150 >150 B40

>150 >150 >150 >150 B41

>150 >150 >150 >150 B42

>150 >150 >150 >150 B43

>150 >150 >150 >150 B44

>150 >150 >150 >150 B45

>150 >150 >150    91 B46

>150 >150 >150 >150 B47

>150 >150 >150 >150 B48

>150 >150   150   150 B49

>150 >150 >150 >150 B50

>150 >150 >150 >150 B51

>150 >150 >150 >150 B52

>150 >150 >150 >150 B53

>150 >150 >150 >150 B54

>150 >150 >150 >150 B55

>150 >150 >150   150 B56

>150 >150 >150 >150 B57

>150 >150 >150 >150 B58

>150 >150 >150 >150 B59

>150 >150 >150    33 B60

>150 >150 >150 >150 B61

>150 >150 >150 >150 B62

>150 >150 >150 >150 B63

>150 >150 >150 >150 B64

>150 >150 >150 >150 B65

>150 >150 >150 >150 B66

>150 >150 >150 >150 B67

>150 >150 >150 >150 B68

>150 >150 >150 >150 B69

>150 >150 >150 >150 B70

>150 >150 >150 >150 B71

  150    90 >150    91 B72

>150 >150 >150 >150 B73

>150 >150 >150 >150 B74

>150 >150 >150 >150 B75

>150 >150 >150 >150 B76

>150 >150 >150 >150 B77

>150 >150 >150 >150 B78

  250   150 >150    55 B79

>150 >150 >150    91 B80

  250    90 >150 >150 B81

>150 >150 >150 >150 B82

>150 >150 >150 >150 B83

>150 >150 >150 >150 B84

>150 >150 >150 >150 B85

>150 >150 >150 >150 B86

>150 >150 >150 >150 B87

  300 >150 >150 >150 B88

>150 >150 >150 >150 B89

  300 >150 >150    91 B90

>150 >150 >150 >150 B91

>150    90 >150 >150 B92

>150 >150 >150 >150 B93

>150 >150 >150 >150 B94

   17     7    91 >150 B95

>150 >150 >150    55 B96

>150    90 >150 >150 B97

>150 >150 >150 >150 B98

>150   150 >150 >150 B99

>150 >150 >150    55 B100

>150 >150 >150 >150 B101

   70    40   150 >150 B102

  120    90   150    91 B103

  150   150 >150 >150 B104

>150    91 >150    55 B105

>150 >150 >150    91 B106

>150 >150 >150   150 B107

>150 >150 >150 >150 B108

>150 >150 >150 >150 B109

>150    91   150    55 B110

>150 >150 >150 >150 B111

>150   150   150    33 B112

>150 >150 >150 >150 B113

>150 >150 >150 >150 B114

>150 >150 >150 >150 B115

>150 >150 >150 >150 B116

>150 >150 >150 >150 B117

>150 >150 >150 >150 B118

>150 >150 >150 >150 B119

>150 >150 >150 >150 B120

>150 >150 >150 >150 B121

>150 >150 >150 >150 B122

>150 >150 >150   150 B123

>150 >150 >150   150 B124

>150 >150 >150 >150 B125

>150 >150 >150 >150 B126

>150 >150 >150 >150 B127

>150 >150 >150 150 B128

>150 >150 >150 >150 B129

>150 >150 >150 >150 B130

>150 >150 >150 >150 B131

>150 >150 >150 >150 B132

  124    85   150 >150 B133

>150 >150 >150    55 B134

  120 >150 >150 >150 B135

>150 >150 >150 >150 B136

>150 >150 >150 >150 B137

>150 >150 >150 >150 B138

>150 >150 >150 >150 B139

>150 >150 >150 >150 B140

>150 >150 >150 >150 B141

>150 >150 >150 >150 B142

>150 >150 >150 >150 B143

>150 >150 >150 >150 B144

>150 >150 >150 >150 B145

>150, res >150 >150    91 B146

  150    90   150 >150 B147

>150 >150 >150 >150 B148

>150 >150 >150   150 B149

>150 >150 >150 >150 B150

>150 >150 >150 >150 B151

>150 >150 >150 >150 B152

>150 >150 >150 >150 B153

>150 >150 >150 >150 B154

>150 >150 >150 >150 B155

>150 >150 >150 >150 B156

  150   150   150 >150 B157

   20    11    55    91 B158

>150 >150 >150 >150 B159

  500   250 >150 >150 B160

>150 >150 >150 >150 B161

>300 >300 >150 >150 B162

>500   300 >150 >150 B163

>300   300 >150 >150 B164

>300    60 >150 >150 B165

>300    60 >150 >150 B166

>300   250   300 >150 B167

>300 >300 >300 >150 B168

  170   182   410 >150 B169

>300    74 >300 >150 B170

>300 >300 >300 >150 B171

   41    19   110 >150 B172

  170    96 >300 >150 B173

>300 >300 >300 >150 B174

>300 >300 >300 >150 B176

>300 >300 >300 >150 B177

>300 >300 >300 >150 B178

>300 >300 >300    55 B179

>300   230 >300   150 B180

>300 >300 >300 >150 B181

>300 >300 >300 >150 B182

>300 >300 >300    91 B183

>300 >300 >300 >150 B184

>300 >300 >300 >150 B185

>300 >300 >300 >150 B187

>300 >300 >300 >150 B188

>300 >300 >300 >150 B189

>300 >300 >300 >150 B190

>300 >300 >300 >150 B191

>300   300   300 >150 B192

  300    96   300    33 B193

>300   300   300   150 B194

>300   170   300   150 B195

>300   300 >300 >150 B196

>300   300 >300   55 B197

  170    96   300 >150 B198

>300   170   170    91 B199

>300   170   170   150 B200

>300   170   300    91 B201

>300    96   170    91 B202

>300 >300 >300 >150 B203

>300   170 >300 >150 B204

>300 >300 >300 >150 B205

>300 >300 >300 >150 B206

>300 >300 >300 >150 B207

>300 >300 >300 >150 B208

>300 >300 >300 >150 B209

>300 >300 >300 >150 B210

>300 >300 >300 >150 B211

>300   300   300 >150 B212

>300 >300 >300 >150 B213

>300 >300 >300 >150 B214

>300 >300 >300 >150 B215

>300 >300 >300 >150 B216

>300 >300 >300 >150 B217

>300 >300 >300 >150 B218

>300 >300 >300 >150 B219

>300 >300 >300 >150 B220

>300 >300 >300 >150 B221

  300   150   220   150 B222

>300 >150 >300 >150 B223

>300 >150 >300 >150 B224

>300 >150 >300 >150 B225

>300 >150   300 >150 B226

   54    33    54    33 B227

  170    12   170   150 B228

  170    20   300    91 B229

  170    7    96    33 B230

   96    4    96    55 B231

  300    54 >300 >150 B232

  170    17    96    91 B233

  300    10   170    91 B234

>300    10    31    55 B235

   96    96 >300 >150 B236

   54    17   300   150 B237

>300   170 >300 >150 B238

>300    10    54    55 B239

>150    20 >150 >150 B240

>150    7 >150   150 B241

  150    4 >150 >150 B242

>150    12 >150 >150 B243

>150    12 >150 >150 B244

   91    3   150   150 B245

  150    4   150   150 B246

>150    12 >150    91 B247

  150    2    91 >150 B248

>150    20 >150 >150 B249

>150 >150 >150 >150 B250

>150    12 >150 >150 B251

   91    7    91 >150 B252

>150    4   150   150 B253

  150    37 >150 >150 B254

>150 >150 >150 >150 B255

>150    84 >150 >150 B256

>150   150 >150 >150 B257

>150    67 >150 >150 B258

>150   100 >150 >150 B259

>150   125 >150 >150 B260

>150    7 >150    91 B261

>150    4 >150   150 B262

  150    12    91    55 B263

>150    3 >150    91 B264

  150    3   150 >150 B265

  150    3    91    91 B266

  150    2    33    55 B267

>150    7 >150    91 B268

>150    7 >150    91 B269

>150    7    55 >150 B270

>150    20 >150 >150 B271

  150    3    55    55 B272

>150    12 >150   150 B273

>150    4 >150   150 B274

  150    7   150 >150 B275

  150    4   91 >150 B276

>150    4 >150 >150 B277

>150    4 >150 >150 B278

>150    12 >150 >150 B279

>150    12 >150 >150 B280

  150    12   150 >150 B281

>150    4    91    91 B282

>150    3 >150  150 B283

   91    7    91   150 B284

>150    7 >150 >150 B285

   91    55 >150 >150 B286

   91    3    91    33 B287

  150    3    91   150 B288

>150    3   150    91 B289

   91    3   150   150 B290

>150    33 >150 >150 B291

   91    12 >150 >150 B292

>150    4 >150   150 B293

  150    4 >150 >150 B294

>150    7 >150 >150 B295

>150    4 >150   150 B296

   91    7 >150 >150 B297

>150    7   150 >150 B298

>150    12 >150 >150 B299

  150    4   150 >150 B300

>150    12 >150 >150 B301

>150    12 >150 >150 B302

  150  <1   150    55 B303

>150    7 >150    91 B304

>150    3 >150    91 B305

>150    3    91   150 B306

>150    12 >150 >150 B307

>150    20 >150 150 B308

>150    4   150 >150 B309

>150    33 >150 >150 B310

>150    55 >150 >150 B311

>150    7 >150 >150 B312

>150    7 >150 >150 B313

>150    7 >150 >150 B314

  150    4    91   150 B315

   91   150   150 >150 B316

>150    7 >150 >150 B317

   91    3    91    55 B318

>150    7 >150   150 B319

   33    12 >150   150 B320

>150    20 >150 >150 B321

>150    55 >150 >150 B322

  150    4   150 >150 B323

>150    4 >150   150 B324

>150    7 >150 >150 B325

>150    4   150    91 B326

>150    12 >150    55 B327

>150    7 >150 >150 B328

>150    55 >150   150 B329

>150    33 >150 >150 B330

>150    33 >150 >150 B331

>150    33 >150 >150 B332

>150 >150 >150 ND B333

>150    7 >150 >150 B334

>150    7 >150 >150 B335

   55    4   150 >150 B336

>150    33 >150 >150 B337

   55    4   150 >150 B338

   91    12 >150 >150 B339

>300   200 >300 >150 B340

>150    55 >150 >150 B341

>150    7 >150   150 B342

  150    4   150    91 B343

  150    4   150 >150 B344

  150    91    91   150 B345

>150    20    33 >150 B346

>150    4    12 >150 B347

  150    4 >150 >150 B348

>150 >150 >150   150 B349

>150 >150 >150 >150 B350

>150 >150 >150 >150 B351

>150 >150 >150 >150 B352

   91    91   150    91 B353

>150 >150 >150 >150 B354

>150   150 >150   150 B355

>150 >150 >150 >150 B356

>150 >150 >150 >150 B357

  150    20    91    91 B358

>150    20 >150 >150 B359

>150    12   150 >150 B360

>150 >150 >150 >150 B361

   91    4    91 >150 B362

  150    7   150 >150 B363

  150    3   150 >150 B364

  150    3   150    91 B365

>150    5 >150 >150 B366

  150   150 >150 >150 B367

  150    5   150 >150 B368

>150    20 >150 >150 B369

>150    3 >150 >150 B370

>150    12 >150 >150 B371

>150    33 >150 >150 B372

  150    5 >150 >150 B373

>150   150 >150 >150 B374

>150 >150 >150   150 B375

>150 >150 >150 >150 B376

  150    91 >150 >150 B377

   75    2.3   150 >150 B378

   91    7   150   150 B379

>150   150 >150 TBD B380

   33    12 >150 >150 B381

   55    4    55    20.2 B382

   55    3    55    12.2 B383

   55    2    91    12.2 B384

   91    4    55    20.2 B385

   91    2   150    90.9 B386

>150    5    55    20.2 B387

   91    3    55    33.4 B388

  150    7    33    33.4 B389

>150    3    91    33.4 B390

  150    3    55    20.2 B391

  150    3    91    20.2 B392

>150    7   150    33.4 B393

>150    7   150    20.2 B394

  150    3    55    20.2 B395

>150    3    33    20.2 B396

  150    3   150    55.1 B397

>150    5 >150    12.2 B398

>150    91 >150   150 B399

  150    20 >150 >150 B400

>150    55 >150 >150 B401

>150    33 >150 >150 B402

  150    33 >150 >150 B403

>150    7 >150 >150 B404

>150    7   150    20.2 B405

   91    5   150    33.4 B406

>150 >150 >150   150 B407

  150    7 >150 >150 B408

   55    2    55    12.2 B409

   55    3    55    12.2 B410

>150 >150 >150 >150 B411

>150   150 >150    7.4 B412

>150    55 >150    7.4 B413

>150    55 >150    7.4 B414

   20    4   150 >150 B415

>150    55 >150    1.257 B416

>150    55 >150    2.5 B417

>150 >150 >150 >150 B418

>150 >150 >150 >150 B419

>150   150 >150    0.6 B420

>150 >150 >150 >150 B421

>150 >150 >150    55.1 B422

>150   150 >150    2.5 B423

>150    55 >150   150 B424

   33    3   150 >150 B425

>150    33 >150 >150 B426

>150    55 >150    1.7 B427

>150 >150 >150    2.7 B428

>150    55 >150 >150 B429

   55    2    33    20.2 B430

>150 >150 >150    55.1 B431

  150    4 >150 >150 B432

  150    33 >150 >150 B433

  150    3   150 >150 B434

  150    4   150 >150 B435

>150   150 >150 >150 B436

>150    91 >150 >150 B437

  150    4 >150 >150 B438

  150    7 >150 >150 B439

   91    12   150 >150 B440

>150 >150 >150   150 B441

>150    91 >150    33.4 B442

>150   150 >150   150 B445

   55    4   150 >150 B446

   91    7 >150 >150 B448

>150 >150 >150 >150 B449

>150    12 >150 >150 B450

>150   150 >150   150 B451

   55    4   150 >150 B452

>150 >150 >150 >150 B453

>150    20 >150 >150 B454

>150    91 >150 >150 B455

>150    91 >150 >150 B456

>150    33 >150 >150 B457

   33  <1    33  >55 B458

>150    4    20    10 B459

   55    2    91    17 B460

   33  <1    33    10 B461

   33  <1    33    10 B462

>150    4    33    10 B463

>150    4 >150    17 B464

>150    90 >150    2 B465

>150    7    90    20 B466

>150 >150 >150  >55 B467

ND ND ND ND B468

ND ND ND ND B469

ND ND ND ND B470

ND ND ND ND B471

ND ND ND ND B472

ND ND ND ND B473

ND ND ND ND B474

ND ND ND ND B475

ND ND ND ND ND = not determined

Example 17: Combination Therapies

A serious problem for antibacterial use of tRNA synthetase inhibitors asantibiotics is high frequency of resistance. Recently, Anacor'sAnti-LeuS AN3365 failed in clinical trials due to a high frequency ofresistance. The problem of resistance may be overcome by employing acombination of molecules targeting different tRNA synthetases in orderto decrease the frequency of resistance down to the product of twoindependent resistance frequencies. E. coli did not develop resistanceto a combination of anti-LeuS Tavaborole with our dialkylamine B1 inmultiple independent experiments, as shown in FIG. 1 . Experimentaldetails: Cultures of E. coli K-12 were started from single colonies onLB-agar plates and were grown in LB for 36 hours with shaking at 37° C.Following that, 10⁸ cells were plated on LB-agar plates containing B1 orTavaborole alone or in combination adjusted for dose equivalence andincubated at 37° C. for 24 hours.

The teachings of all patents, published applications and referencescited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-74. (canceled)
 75. A compound having the structure of formula (I-A):

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of (C₃-C₈)alkyl, (C₂-C₈)hydroxyalkyl,(C₁-C₈)aminoalkyl, (C₄-C₈)cycloalkyl, aryl, heteroaryl,(CH₃SO₂)(C₁-C₈)alkyl, and di((C₁-C₈)alkyl)amino; each of R², R³, R⁴, andR⁵ is independently selected from H, OH, —NH₂, halide, sulfonamido,(C₁-C₆)alkylsulfonyl, —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl),—C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl, optionallysubstituted (C₁-C₈)alkoxy, optionally substituted (C₁-C₈)aminoalkyl,optionally substituted (C₁-C₈)hydroxyalkyl, optionally substituted(C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)haloalkoxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryloxy, optionally substituted arylalkoxy, optionallysubstituted heteroaryloxy, optionally substituted heteroarylalkoxy,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkoxy, optionally substituted (C₂-C₉)heterocycloalkyl,optionally substituted (C₂-C₉)heterocycloalkoxy,(H₃CSO₂)(C₁-C₈)alkylene, optionally substituted (R^(b)₂NSO₂)(C₁-C₈)alkylene, optionally substituted di((C₁-C₈)alkyl)amino,—NH—CH₂—R⁸, —O—CH₂—R⁸, and —O—CH₂CH₂—O—R⁹; or R² and R³, R³ and R⁴, orR⁴ and R⁵, taken together with the intervening atoms, form an optionallysubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; R⁶is H or (C₁-C₆)alkyl; R⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or(C₃-C₁₀)cycloalkenyl; R⁸ is selected from—C(O)((C₂-C₉)heterocycloalkyl), —C(O)NH((C₁-C₈)alkyl),—C(O)NH(aryl(C₁-C₈)alkyl), —C(O)NH((C₃-C₈)cycloalkyl),—C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl), —C(O)N(CH₃)((C₃-C₈)cycloalkyl),—C(O)N(CH₃)(aryl(C₁-C₈)alkyl), —C(O)NHC(O)NH((C₃-C₈)cycloalkyl),—C(O)NHC(O)NH((C₁-C₈)alkyl), —C(O)NHC(O)NH₂, optionally substitutedheteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole orthiazole, optionally substituted aryloxy(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl,heteroaryl(C₁-C₈)alkyl, (C₂-C₈)alkoxy, (C₃-C₈)hydroxyalkyl,(C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₁-C₈)haloalkoxy(C₁-C₈)alkyl,(C₁-C₈)thioalkoxy(C₁-C₈)alkyl, (CH₃SO₂)(C₁-C₈)alkyl, and((C₁-C₈)alkylC(O))(C₁-C₈)alkyl; R⁹ is selected from (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl,(C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl, and optionally substitutedaryl; and R^(b), independently for each occurrence, is selected from H,optionally substituted (C₁-C₈)alkyl, optionally substituted(C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, andoptionally substituted aryl(C₁-C₈) alkyl.
 76. The compound of claim 75,wherein R⁶ is (C₁-C₆)alkyl.
 77. The compound of claim 76, wherein R⁶ ismethyl.
 78. The compound of claim 75, wherein R⁶ is H.
 79. The compoundof claim 75, wherein R⁷ is optionally substituted cyclohexyl orcyclohexenyl.
 80. The compound of claim 75, wherein R², R³, R⁴, and R⁵are each H.
 81. The compound of claim 75, wherein R¹ is selected fromthe group consisting of aryl and heteroaryl.
 82. A compound having thestructure of formula (I-B):

or a pharmaceutically acceptable salt thereof; wherein: R¹ representsoptionally substituted (R^(b) ₂NSO₂)(C₁-C₈)alkylene; each of R², R³, R⁴,and R⁵ is independently selected from H, OH, —NH₂, halide, sulfonamido,(C₁-C₆)alkylsulfonyl, —OC(O)((C₁-C₈)alkyl), —C(O)O((C₁-C₈)alkyl),—C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH₂, —B(OH)₂,tri((C₁-C₈)alkyl)silyl, optionally substituted (C₁-C₈)alkyl, optionallysubstituted (C₁-C₈)alkoxy, optionally substituted (C₁-C₈)aminoalkyl,optionally substituted (C₁-C₈)hydroxyalkyl, optionally substituted(C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)haloalkoxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryloxy, optionally substituted arylalkoxy, optionallysubstituted heteroaryloxy, optionally substituted heteroarylalkoxy,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkoxy, optionally substituted (C₂-C₉)heterocycloalkyl,optionally substituted (C₂-C₉)heterocycloalkoxy,(H₃CSO₂)(C₁-C₈)alkylene, optionally substituted (R^(b)₂NSO₂)(C₁-C₈)alkylene, optionally substituted di((C₁-C₈)alkyl)amino,—NH—CH₂—R⁸, —O—CH₂—R⁸, and —O—CH₂CH₂—O—R⁹; or R² and R³, R³ and R⁴, orR⁴ and R⁵, taken together with the intervening atoms, form an optionallysubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; R⁶is H or (C₁-C₆)alkyl; R⁷ is optionally substituted (C₃-C₁₀)cycloalkyl or(C₃-C₁₀)cycloalkenyl; R⁸ is selected from—C(O)((C₂-C₉)heterocycloalkyl), —C(O)NH((C₁-C₈)alkyl),—C(O)NH(aryl(C₁-C₈)alkyl), —C(O)NH((C₃-C₈)cycloalkyl),—C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl), —C(O)N(CH₃)((C₃-C₈)cycloalkyl),—C(O)N(CH₃)(aryl(C₁-C₈)alkyl), —C(O)NHC(O)NH((C₃-C₈)cycloalkyl),—C(O)NHC(O)NH((C₁-C₈)alkyl), —C(O)NHC(O)NH₂, optionally substitutedheteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole orthiazole, optionally substituted aryloxy(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl,heteroaryl(C₁-C₈)alkyl, (C₂-C₈)alkoxy, (C₃-C₈)hydroxyalkyl,(C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₁-C₈)haloalkoxy(C₁-C₈)alkyl,(C₁-C₈)thioalkoxy(C₁-C₈)alkyl, (CH₃SO₂)(C₁-C₈)alkyl, and((C₁-C₈)alkylC(O))(C₁-C₈)alkyl; R⁹ is selected from (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl,(C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl, and optionally substitutedaryl; and R^(b), independently for each occurrence, is selected from H,optionally substituted (C₁-C₈)alkyl, optionally substituted(C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, andoptionally substituted aryl(C₁-C₈) alkyl.
 83. The compound of claim 82,wherein R⁶ is (C₁-C₆)alkyl.
 84. The compound of claim 82, wherein R⁶ ismethyl.
 85. The compound of claim 82, wherein R⁶ is H.
 86. The compoundof claim 82, wherein R⁷ is optionally substituted cyclohexyl orcyclohexenyl.
 87. The compound of claim 82, wherein R², R³, R⁴, and R⁵are each H.
 88. A compound having the structure of formula (I-C):

or a pharmaceutically acceptable salt thereof; wherein: R¹ is selectedfrom the group consisting of —O—CH₂—R⁸ and —O—CH₂CH₂—O—R⁹; each of R²,R³, R⁴, and R⁵ is independently selected from H, OH, —NH₂, halide,sulfonamido, (C₁-C₆)alkylsulfonyl, —OC(O)((C₁-C₈)alkyl),—C(O)O((C₁-C₈)alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl),—C(O)NH₂, —B(OH)₂, tri((C₁-C₈)alkyl)silyl, optionally substituted(C₁-C₈)alkyl, optionally substituted (C₁-C₈)alkoxy, optionallysubstituted (C₁-C₈)aminoalkyl, optionally substituted(C₁-C₈)hydroxyalkyl, optionally substituted (C₁-C₈)haloalkyl, optionallysubstituted (C₁-C₈)haloalkoxy, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryloxy, optionallysubstituted arylalkoxy, optionally substituted heteroaryloxy, optionallysubstituted heteroarylalkoxy, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₁₀)cycloalkoxy, optionally substituted(C₂-C₉)heterocycloalkyl, optionally substituted(C₂-C₉)heterocycloalkoxy, (H₃CSO₂)(C₁-C₈)alkylene, optionallysubstituted (R^(b) ₂NSO₂)(C₁-C₈)alkylene, optionally substituteddi((C₁-C₈)alkyl)amino, —NH—CH₂—R⁸, —O—CH₂—R⁸, and —O—CH₂CH₂—O—R⁹; or R²and R³, R³ and R⁴, or R⁴ and R⁵, taken together with the interveningatoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, orheterocycloalkyl group; R⁶ is H or (C₁-C₆)alkyl; R⁷ is optionallysubstituted (C₃-C₁₀)cycloalkyl or (C₃-C₁₀)cycloalkenyl; R⁸ is selectedfrom —C(O)((C₂-C₉)heterocycloalkyl), —C(O)NH((C₁-C₈)alkyl),—C(O)NH(aryl(C₁-C₈)alkyl), —C(O)NH((C₃-C₈)cycloalkyl),—C(O)NH((C₃-C₈)cycloalkyl(C₁-C₈)alkyl), —C(O)N(CH₃)((C₃-C₈)cycloalkyl),—C(O)N(CH₃)(aryl(C₁-C₈)alkyl), —C(O)NHC(O)NH((C₃-C₈)cycloalkyl),—C(O)NHC(O)NH((C₁-C₈)alkyl), —C(O)NHC(O)NH₂, optionally substitutedheteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole orthiazole, optionally substituted aryloxy(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heterocycloalkyl(C₂-C₈)alkyl,heteroaryl(C₁-C₈)alkyl, (C₂-C₈)alkoxy, (C₃-C₈)hydroxyalkyl,(C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₁-C₈)haloalkoxy(C₁-C₈)alkyl,(C₁-C₈)thioalkoxy(C₁-C₈)alkyl, (CH₃SO₂)(C₁-C₈)alkyl, and((C₁-C₈)alkylC(O))(C₁-C₈)alkyl; R⁹ is selected from (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl,(C₁-C₈)alkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl, and optionally substitutedaryl; and R^(b), independently for each occurrence, is selected from H,optionally substituted (C₁-C₈)alkyl, optionally substituted(C₁-C₈)haloalkyl, optionally substituted (C₁-C₈)hydroxyalkyl, optionallysubstituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkyl(C₁-C₈)alkyl, optionally substituted aryl, andoptionally substituted aryl(C₁-C₈) alkyl.
 89. The compound of claim 88,wherein R⁶ is (C₁-C₆)alkyl.
 90. The compound of claim 89, wherein R⁶ ismethyl.
 91. The compound of claim 88, wherein R⁶ is H.
 92. The compoundof claim 88, wherein R⁷ is optionally substituted cyclohexyl orcyclohexenyl.
 93. The compound of claim 88, wherein R², R³, R⁴, and R⁵are each H.
 94. The compound of claim 88, wherein R¹ is —O—CH₂—R⁸ and R⁸is optionally substituted heteroaryl wherein the heteroaryl is not4-pyridinyl, benzimidazole, or thiazole.
 95. A method of treating abacterial infection in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of claim 75.